Pulsatile Balloon Catheter Systems and Methods of Using the Same

ABSTRACT

Pulsatile balloon catheter systems are provided. Aspects of the systems include: a pulse generator; and a balloon catheter assembly operably connected to the pulse generator. In embodiments, the balloon catheter assembly includes: a proximal connector operably connecting the balloon catheter assembly to the pulse generator and configured to transduce a first pulse energy generated by the pulse generator to a second pulse energy; a distal balloon; and a catheter component, where the catheter component includes a fluidic passage operably positioned between the proximal connector and the distal balloon, which passage is configured to propagate the second pulse energy from the proximal connector along the fluid passage to the distal balloon. Also provided are balloon catheter assemblies and kits that include the same. Also provided are systems and methods for assessing vessel compliance in-vivo. Also provided are systems and methods for determining system state of balloon catheter systems. The systems, assemblies and kits find use in a variety of different applications, including balloon angioplasty applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International ApplicationNo. PCT/US2022/014785 filed Feb. 1, 2022, which claims priority to thefiling dates of: U.S. provisional patent application Ser. No. 63/274,832filed Nov. 2, 2021; U.S. provisional patent application Ser. No.63/241,295 filed Sep. 7, 2021; and U.S. provisional patent applicationSer. No. 63/145,641 filed Feb. 4, 2021; the disclosures of whichapplications are incorporated herein by reference in their entirety.

INTRODUCTION

This section provides background information related to the presentdisclosure which is not necessarily prior art. This section alsoprovides a general summary of the disclosure and is not a comprehensivedisclosure of its full scope or all of its features.

Ischemic heart disease, the number one cause of death in the world, iscaused by atherosclerotic plaque build-up within human vasculature.Worldwide, these diseases represent 84.5% of cardiovascular deaths and28.2% of overall mortality. Ischemic heart disease is developed througha mechanism called atherosclerosis, which is the accumulation of fattyand calcified materials that cause stenosis, the narrowing of thearterial lumen. Both the coronary and peripheral arteries may sufferfrom atherosclerotic plaque accumulation. The plaque buildup fromatherosclerosis limits blood flow through these arteries and can lead tomajor adverse cardiovascular events such as myocardial infarction, limbamputation, and mortality. In the early stages of atherosclerosis,plaques are soft and fatty, but as time and the disease progress, theseplaques physically harden, or calcify. Calcified plaque (CP) thatdevelops in the innermost layer of the artery wall occurs mostfrequently. These CPs result from the deposition and remodeling ofcalcium hydroxyapatite, a process that mimics bone formation.CP-burdened vessels have reduced vascular elasticity and impaired vesselperfusion. Because of this reduced compliance and perfusion, CPs areassociated with an increased risk of mortality and other adverse events.

While many patients with CP are asymptomatic, a substantial number ofpatients develop symptoms and signs related to ischemia and undergoendovascular or surgical repair. Given its lower morbidity, endovascularapproaches are generally favored. However, CP-burdened vessels posespecial challenges for effective intravascular treatments. To treatCP-burdened vessels, a series of devices are often used. The CP-lesionis first pre-dilated using balloon angioplasty (BA). During BA, aballoon is advanced to the affected artery and is expanded to dilate aplaque-burdened vessel to restore normal blood flow. This pre-dilationstep must be successful before secondary therapies such as drug-coatedballoons or stents can be successfully used. For successfulpre-dilation, BA must mechanically fracture the CP to ensure thelong-term opening, or patency, of the vessel and to re-establish theelasticity of the surrounding healthy vessel. Often, high-pressure,non-compliant balloons are used to achieve success. However, because ofthe strength of CP, full balloon expansion is often restricted, and theCP remains unfractured. Without sufficient balloon expansion and CPfracture, the vessel remains with a residual stenosis limitingdownstream blood flow indicating a poor outcome, a high risk ofimmediate or long-term failure, and the need for additional procedures.To ensure patency of diseased vessels, the high rupture strength of theCP must be overcome.

During standard BA, a pressurized catheter balloon is used to fractureatherosclerotic plaques and expand them into artery walls tore-establish normal blood flow in stenosed arteries. Typically, theballoon is pressurized via a manually actuated screw-driven syringe,which converts rotations of a physician-facing handle into adisplacement of the syringe piston. The handle of the syringe is rotatedby a clinician until the pressure within the system reaches a desiredpressure, or the physician senses fracture of the calcified plaque.During treatment, the physician can sense if the calcified plaque hasfractured in two ways: (1) from the outline of the balloon underfluoroscopy, a medical imaging technique commonly used in cardiovascularprocedures, and (2) from a reduction in pressure within the hydraulicsystem as indicated by a pressure gauge. During angioplasty procedures,a radiopaque dye (i.e., contrast agent) is introduced into the balloon,which under fluoroscopy, illuminates the outline of the balloon andarterial walls. When the plaque is intact and the balloon ispressurized, the balloon assumes a characteristic dog-bone shape inwhich the proximal and distal edges are unrestricted to expand but themiddle is obstructed by the plaque. The shape of the dog-bone informsthe clinician of the severity and distribution of the plaque. In somescenarios, the entire artery is diseased, and the balloon remainsuniformly unexpanded and does not achieve a full diameter. In otherscenarios, the balloon may have indentation in one or more planessuggesting an eccentric plaque. A more uniformly expanded balloonindicates to the physician that the plaque has been treated. The secondmethod used to sense plaque fracture is indicated by the pressure gaugeattached to the balloon. When treating severe and/or circumferentiallydistributed plaque, pressure is increased in the balloon until theplaque fractures. Prior to fracture of the plaque, the balloon maintainsthe previously described restricted shape (e.g., a dog bone-shape). Uponfracture, the plaque no longer restricts the balloon expansion, and theballoon expands the plaque into the elastic artery. With this balloonexpansion, the volume of the balloon increases, transforming it from arestricted shape (e.g., a dog-bone shape) into a fully expandedcylindrical shape. This volume increase causes the pressure in theballoon to drop, a change that may be visualized or sensed from theconnected pressure gauge.

To overcome the rupture strength of CP, angioplasty balloons are oftenused in an off-label (i.e., not FDA-approved) fashion to aggressivelyexpand CP-burdened vessels. In these cases, balloons are pressurizedpast their rated burst pressures (i.e., >20-40 ATM of pressure) toachieve sufficient balloon expansion that dilates the artery. Theseaggressive procedures subject patients to increased risks such asballoon rupture in 21% of cases, vessel dissection in 76% of cases andrestenosis (i.e., post-procedure vessel re-narrowing) in 20-30% ofcases. Other treatment strategies that attempt to fracture CP includecutting and scoring BA and Shockwave lithotripsy BA. Cutting balloons,which are balloons surrounded by sharp-tipped metallic blades, andscoring balloons, which are balloons constrained in a metallic cage, aimto generate stress concentrations for CP fracture. During balloonpressurization, the metallic blades or cage can become embedded insoft-tissue or CP causing major procedural issues. Poor outcomes havebeen associated with these balloons including restenosis in 20-30% ofcases and major adverse events such as vessel perforation, myocardialinfarction, or death in 6% of cases. Shockwave BA employs low-pressureballoons with embedded shockwave-generating lithotripters. Short-termefficacy and safety with lithotripsy devices have been demonstratedthrough clinical trials; however, recent case reports have shown thatthese >50 ATM cavitation explosions lead to dangerous arterialdissections and perforations. Another commonly employed treatment for CPis atherectomy, a technique that uses grinding to debulk CP. However,atherectomy is more challenging technically and grinds CP andsurrounding healthy tissue, which can lead to long-term vessel injury.

In addition to the concern for patient outcomes, endovascular proceduresand surgeries can significantly affect the treating physician. Over aninterventional cardiologists' career, s/he can be exposed to anestimated 50 mSv-200 mSv of ionizing radiation, which is equivalent to2,500-10,000 chest X-rays. With this amount of radiation exposure,treating physicians are exposed to serious long-term health issues suchas cancer, cataracts, cognitive function, and reproductive effects. Tomitigate the risks of ionizing radiation backscatter, physicians wearpersonal protective equipment (PPE) (e.g., heavy lead suits) forprotection. Because of this PPE, a statistically significant group ofinterventional cardiologists reported musculoskeletal injuries that mayhave the effect of shortening careers.

There continues to be a need for improved balloon angioplasty devicesand methods of use.

SUMMARY

Pulsatile balloon catheter systems are provided. Aspects of the systemsinclude: a pulse generator; and a balloon catheter assembly operablyconnected to the pulse generator. In embodiments, the balloon catheterassembly includes: a proximal connector operably connecting the ballooncatheter assembly to the pulse generator and configured to transduce afirst pulse energy generated by the pulse generator to a second pulseenergy; a distal balloon; and a catheter component, where the cathetercomponent includes a fluidic passage operably positioned between theproximal connector and the distal balloon, which passage is configuredto propagate the second pulse energy from the proximal connector alongthe fluid passage to the distal balloon. Also provided are aspects ofrobotic and/or stand-alone balloon catheter systems. Also provided areballoon catheter assemblies and kits that include the same. Alsoprovided are systems and methods for assessing vessel compliancein-vivo. Also provided are systems and methods for determining systemstate of balloon catheter systems. The systems, assemblies and kits finduse in a variety of different applications, including balloonangioplasty applications.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a schematic diagram of a system according to anembodiment of the invention.

FIG. 2 provides a view of a catheter balloon assembly according to anembodiment of the invention.

FIGS. 3A to 3H provide various views of a proximal connector of aballoon catheter assembly according to an embodiment of the invention.

FIGS. 4A to 4F provide various views of a hand-held actuator of a pulsegenerator according to an embodiment of the invention.

FIG. 5 provides an example of a pressure-volume relationship for anunrestrained 4 mm diameter×20 mm length balloon.

FIG. 6 provides two examples of the experimentally measured pressure inthe balloon and force output from the balloon of FIG. 5.

FIG. 7A provides an illustration of pressure-volume relationships undervarious physical constraints. FIG. 7B: (Panels A-B) Example fluoroscopyimages of a focal lesion (shown by arrows). (Panels C-D) A balloon isinserted across the lesion and pressurized. In view (Panel C), theballoon appears to be expanded. However, in a normal projection image(Panel D), the balloon is under-expanded. FIG. 7C provides an example ofmeasurements of changes in vessel compliance obtained during treatmentusing a system according to the present invention.

FIG. 8 provides a schematic diagram of a system according to anembodiment of the invention configured to assess vessel compliancein-vivo.

FIGS. 9A and 9B provide various views of a proximal connector of aballoon catheter assembly according to an embodiment of the inventionconfigured to assess vessel compliance in-vivo.

FIG. 10 provides an example of analytical and experimental relationshipbetween membrane position, balloon volume and Hall sensor output.

FIG. 11 presents a circuit diagram of an exemplary electronic circuitfor monitoring system state according to the present invention.

FIG. 12A shows results of operation of an exemplary electronic circuitfor monitoring system state according to the present invention.

FIG. 12B depicts example behavior of pressure and volume measurementsfrom an intact (i.e., not leaking) catheter of a system according to thepresent invention during treatment.

FIG. 12C depicts example behavior of pressure and volume measurementsfrom a completely failed catheter of a system according to the presentinvention during treatment.

FIG. 12D depicts example behavior of pressure and volume measurementsfrom a leaking catheter of a system according to the present inventionduring treatment.

FIG. 13 provides a schematic of an embodiment of an alternativeconnector configured to deliver a high-volume, low-frequency, andlow-pressure pulse.

FIG. 14A is a schematic view of an elastic conduit (e.g., artery) havinga hardened material (e.g., calcified plaque) embedded therein to betreated by the dynamic balloon angioplasty (DBA) techniques and devicesaccording to some embodiments of the present teachings. FIG. 14B is aschematic view of the elastic conduit of FIG. 14A having a DBAangioplasty balloon navigated to the affected region andpre-pressurized. FIG. 14C is a schematic view of the elastic conduit ofFIG. 14A having the DBA angioplasty balloon cycled to a low pressure.FIG. 14D is a schematic view of the elastic conduit of FIG. 14A havingthe DBA angioplasty balloon cycled to a high pressure. FIG. 14E is aschematic view of the elastic conduit of FIG. 14A having the hardenedmaterial fractured according to the principles of the present teachings.

FIG. 15 provides a depiction of a pulsatile treatment plan in accordancewith an embodiment of the invention.

FIG. 16 shows the procedural steps of an autonomous angioplastyprocedure performed with embodiments of the invention.

FIG. 17 shows a graphical user interface (GUI) that with which anoperator may interface during an autonomous angioplasty procedure ofembodiments of the invention, such as illustrated in FIG. 16.

FIG. 18 provides a photograph of a balloon catheter assembly accordingto an embodiment of the invention.

FIG. 19 provides various photographic views of the proximal connector ofthe balloon catheter assembly of FIG. 18.

FIG. 20 provides a picture of a balloon catheter system according to anembodiment of the invention.

DETAILED DESCRIPTION

Pulsatile balloon catheter systems are provided. Aspects of the systemsinclude: a pulse generator; and a balloon catheter assembly operablyconnected to the pulse generator. In embodiments, the balloon catheterassembly includes: a proximal connector operably connecting the ballooncatheter assembly to the pulse generator and configured to transduce afirst pulse energy generated by the pulse generator to a second pulseenergy; a distal balloon; and a catheter component, where the cathetercomponent includes a fluidic passage operably positioned between theproximal connector and the distal balloon, which passage is configuredto propagate the second pulse energy from the proximal connector alongthe fluid passage to the distal balloon. Also provided are aspects ofrobotic balloon catheter systems. Also provided are balloon catheterassemblies and kits that include the same. The systems, assemblies andkits find use in a variety of different applications, including balloonangioplasty applications.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

While the apparatus and method has or will be described for the sake ofgrammatical fluidity with functional explanations, it is to be expresslyunderstood that the claims, unless expressly formulated under 35 U.S.C.§ 112, are not to be construed as necessarily limited in any way by theconstruction of “means” or “steps” limitations, but are to be accordedthe full scope of the meaning and equivalents of the definition providedby the claims under the judicial doctrine of equivalents, and in thecase where the claims are expressly formulated under 35 U.S.C. § 112 areto be accorded full statutory equivalents under 35 U.S.C. § 112.

In further describing various aspects of the invention, the systems andcomponents thereof are described first in greater detail, followed by areview of methods of using the systems as well as kits for practicingthe subject methods.

Pulsatile Balloon Catheter Systems

As summarized above, pulsatile balloon catheter systems are provided.Pulsatile balloon catheter systems of embodiments of the invention areconfigured to provide a distal end balloon that imparts pulsatile energyto internal tissue (e.g., luminal vascular tissue, such as an arterialinner wall location) in contact therewith, e.g., in the form ofincreasing and decreasing pressure applied at a desired frequency, dutycycle, and amplitude to the internal tissue in contact therewith. Asused herein, the frequency is the number of full pressure pulse cycles(peak-to-peak) per unit time; the duty cycle is the percentage of timeallocated to the high-pressure segment of a single pressure cycle; andthe amplitude is the difference between the maximum and minimumpressure. As the energy imparted by the balloon to the internal tissueis pulsatile, it changes (e.g., increases and decreases) at a defined ordetermined frequency and duty cycle. During BA treatment, blood flowdistal to the distal end balloon may be occluded, which may limittreatment time. To achieve a successful treatment within this time, thepulsatile frequency and amplitude must impart sufficient energy to thetissue to treat it. While the frequency of pulsatile energy imparted bythe balloon to tissue associated therewith may vary, in some instancesthe frequency is high frequency, ranging in some instances from 0 to 100Hz, such as 0 to 25 Hz. Similarly, the duty cycle of pulsatile energyimparted by the balloon to tissue may vary ranging in some instancesfrom 10% to 100%, such as 60% to 80%. Amplitude of pulsatile energyimparted by the balloon to tissue may vary ranging in some instancesfrom an internal balloon pressure from 0-100 ATM, such as 0-30 ATM.described below, during a given procedure, the frequency may vary overthe course of the procedure, i.e., not remain constant, as desired.

Pulsatile energy, when exposed to diseased luminal vascular tissue, iseffective in treating diseased tissue, such as CP tissue, while reducingthe negative effects on surrounding healthy tissue. Importantcharacteristics of pulsatile energy for achieving successful treatmentsmay include the frequency and amplitude of the delivered pulsatileenergy. In embodiments, such pulsatile energy can enable the safe,controlled, fatigue fracture of CP-lesions. Fatigue fracture is theprocess of cyclically loading a structure below the pressure that yieldsinstantaneous failure. Whereas conventional treatments apply dangeroushigh-pressure bursts to the vessel that may create dissections andperforations, pulsatile angioplasty employs lower pressurehigh-frequency oscillations in an amplifier balloon to initiatelow-pressure fatigue fracture of CP-lesions.

Input Signal Versus Output Signal in a Mechanical System

The described embodiments are dynamic physical systems, in which theoutput of the system (e.g., actual frequency, duty cycle, and amplitude)is governed by the system input (e.g., desired frequency, duty cycle,and amplitude) and the system characteristics (e.g., catheter length,friction, and flow channel lumen diameter). Embodiments of the systemsare configured for generating controlled mechanical lithotripsy pulsesin an angioplasty balloon such that the system output tracks, in someinstances with minimal attenuation, the commanded, or desired, inputsignal. Signal attenuation is the reduction in amplitude in the systemoutput versus the input because of the characteristics of the physicalsystem. For successful treatment, minimal attenuation, in that theoutput pulsatile energy remains substantially similar, e.g., in terms offrequency, duty cycle, and/or amplitude, to the input pulsatile energyas it propagates from the system input (e.g., proximal connector) to thesystem output (e.g., the distal balloon), is required. As such, in someinstances any change in frequency, if present at all, between theproximal connector and distal balloon would be 30% or less, such as 5%or less. In some instances, any change in amplitude, if present at all,of the pulsatile energy between the proximal connector and distalballoon would be 30% or less, such as 5% or less. In some instances, anychange in duty cycle, if present at all, of the pulsatile energy betweenthe proximal connector and distal balloon would be 30% or less, such as5%.

Prior art (e.g., as described in WO 2017/168145A1; US 2019/0000491A1;U.S. Pat. No. 6,348,048 B1; WO 2001/010491A2 and U.S. Pat. No. 8,574,248B2) in this field has described methods of generating pressure pulses inan angioplasty balloon. However, because of system characteristics, theprior art either is required to proceed at low frequencies to achievefull pressure pulses or suffers from severe attenuation of the signals.In the case of low frequency pressure pulses, the balloon does notgenerate sufficient pulses in the vessel to achieve any improvedtreatment outcome. In the case of high frequency pressure pulses, thesystem output (i.e., the balloon pulse) does not track system inputsand/or the system output is so severely attenuated by the systemcharacteristics that the treatment is ineffective. In other cases, thesystems are designed such that the input pressure itself is generatedwith such high frictional losses (e.g., a piston pump system) that highfrequency input pressure pulses are attenuated before being transmittedto the proximal connector.

As summarized above, pulsatile balloon catheter systems, whichrepresents a mechanical system, according to embodiments of theinvention include a pulse generator and a balloon catheter assemblyoperably connected to the pulse generator. The pulse generator of thesystems is a component which is configured to generate a first pulsatileenergy that can be transduced by the balloon catheter assembly to asecond pulsatile energy, e.g., as described in greater detail below. Theballoon catheter assembly is configured to receive the first pulsatileenergy provided by the pulse generator and transduce it to a secondpulsatile energy that may be received by the distal balloon to impartpulsatile energy to an internal tissue location, as described above,such as for use in DBA or lithotripsy applications, e.g., as describedin greater detail below, as well as for use in final post-dilatation ofthe vessel, for example in one treatment comprising both applications.That is, embodiments of the present invention may be used first to applypressure pulses to luminal tissue, such as a vessel, to crack calcium(i.e., CP-affected tissue) and then to subsequently expand the vesselusing traditional, non-compliant balloon post-dilatation, e.g., asdescribed in greater detail below. Embodiments of the pulse generatorand the balloon catheter assembly are now reviewed in greater detail.

Pulse Generator

The first pulsatile energy may vary as desired, where examples of firstpulsatile energy include, but are not limited to: pulsatile pressureenergy, pulsatile mechanical energy, pulsatile electromagnetic energy,and the like. As the first pulsatile energy is pulsatile, the magnitudeof the first energy changes or modulates over time, e.g., according to adetermined or known, e.g., predetermined, frequency, according to theuser, and/or according to treatment progression (as described below).While the frequency of the first pulsatile energy may vary, in someinstances the frequency is high frequency, ranging in some instancesfrom a low frequency to a high frequency, such as greater than 0 to 100Hz, such as 2 to 25 Hz. As described below, during a given procedure,the frequency amplitude and/or duty cycle may vary over the course ofthe procedure, i.e., not remain constant, as desired (e.g., as describedin conjunction with FIG. 6, below). The frequency, amplitude, and/orduty cycle also may vary depending on the type of balloon catheter(e.g., balloon length and/or diameter, shaft length), treatment type,lesion stiffness, etc. The frequency, amplitude, and/or duty cycle alsomay vary depending on user inputs, negative feedback from measurements,and/or positive feedback from system modeling.

Pulse generators of embodiments of the invention include potentialsources configured to provide energy which may be regulated as desiredby a regulator and an oscillator to provide for the pulsatile aspect ofthe first pulsatile energy. Any convenient potential source may beemployed, where examples of potential sources include voltage sources,pressure sources, electromagnetic sources, electric field sources,chemical sources, and the like. In some embodiments, the potentialsource is a pressure source, where examples of suitable pressure sourcesinclude, but are not limited to: compressed gas cylinders, compressors,and the like. Where desired, the potential source may be operablycoupled to a regulator, which serves to modulate energy to a suitableform so that it may be further acted upon by the oscillator. Forexample, where the potential source is a high-pressure gas source, e.g.,as may be employed in a pneumatic pulse generator, the regulator mayserve to regulate the pressure of the gas to a suitable value that canbe input to the oscillator. In addition to the potential source andregulator, the pulse generators may include an oscillator. In suchinstances, the oscillator is used to modulate the magnitude and timingthereof of the potential energy from the potential source to provide forthe desired first pulsatile energy.

The disparate components of the pulse generator may be present in asingle housing or provided as two or more distinct, operably connectedunits. In some instances, at least some of the pulse generatorcomponents are present in a unit that is configured to be hand-held. Insuch instances, the hand-held component, e.g., hand-held actuator, isdesigned to be held and operated in a single adult human hand. While theform factor of such hand-held units may vary as desired, in someinstances, such units have a general diameter and/or width ranging from20 to 150 mm, such as 50 to 80 mm and length ranging from 50 to 300 mm,such as 100 to 200 mm, and a mass ranging from 100 to 2000 g, such as500 to 750 g. For example, a pulse generator may include a first consolecomponent that houses the potential source and regulator, and a secondhand-held actuator that includes the oscillator and an actuator for theoscillator, e.g., a manipulatable button. The hand-held actuator mayinclude an electrical connector for providing electrical connection tovarious components, of the balloon catheter assembly, as desired. Forexample, the electrical connector may be used to receive data regardingdiaphragm position, memory, and/or pressure and to provide power tothese sensors, where examples of such are further described below.

In some instances, at least some of the pulse generator components arepresent in a mountable unit that is configured to be positioned or fixedon the operating table near a patient so that the physician does notneed to be physically present to treat the patient. In such instances,the mountable unit is designed to be easily clamped, fixed, orindependently stable on the operating table and can be operated by adistant control unit. In such instances, the mountable unit may includea communicator that provides for communication between the unit and thedistal control unit, which may be implemented by any desired hardwareand/or software configuration, and may be configured to communicateusing wired or wireless protocols. Pulse generators employed in systemsof the invention may be configured to be reusable or single use, asdesired. Pulse generators employed in systems of the invention may beconfigured to receive a sterile sleeve such that the generator may beused while not contaminating the sterile field of the operating room.Further details regarding pulse generators and components thereof, e.g.,potential sources, oscillators, regulators, etc., that may be employedin embodiments of the present invention are provided in United StatesPublished Patent Application Publication No. 20200046949 as well aspending PCT Application Serial No. PCT/US2020/055458; the disclosures ofwhich are herein incorporated by reference.

Balloon Catheter Assembly

As summarized above, in addition to the pulse generator, systems of theinvention include a balloon catheter assembly. The balloon catheterassembly is configured to receive first pulsatile energy from the pulsegenerator and transduce it to a second pulsatile energy that may bepropagated along the length of the assembly, e.g., along the fluid,e.g., liquid, passageway thereof, to a distal balloon. As the ballooncatheter assembly transduces the first pulsatile energy to a secondpulsatile energy, it changes the form of the pulsatile energy in someway. Examples of changes to the form of energy that may be made by theproximal connector include, but are not limited to: gas pressure and/orflow to liquid pressure and/or flow, mechanical potential and/or kineticenergy to fluid pressure and/or flow, optical potential and/or kineticenergy to fluid pressure and/or flow, electric field potential and/orkinetic energy to fluid pressure and/or flow, magnetic potential and/orkinetic energy to fluid pressure and/or flow, and the like. For example,where the first pulsatile energy is a pneumatic first pulsatile energy,the balloon catheter assembly may be configured to transduce thepneumatic first pulsatile energy to a second hydraulic pulsatile energythat may be propagated from the proximal end of the balloon catheterassembly to the distal end of the balloon catheter assembly, which is anexample of gas to liquid transduction of the pulsatile energy. In someinstances, the balloon catheter assembly propagates the second pulsatileenergy from the proximal to distal end with little, if any attenuation,where the magnitude of any attenuation, if present, does not exceed 30%reduction, and in some instances does not exceed 5%, e.g., as describedabove.

In some instances, the balloon catheter assembly includes: (i) aproximal connector operably connecting the balloon catheter assembly tothe pulse generator and configured to transduce a first pulse energygenerated by the pulse generator to a second pulse energy; (ii) a distalballoon; and (iii) a catheter component that includes a fluidic passageoperably positioned between the proximal connector and the distalballoon.

The proximal connector is a component of the assembly located proximallyin the assembly, e.g., at the proximal end or near the proximal end,e.g., within 1 cm or closer to the proximal end, where the proximalconnector is configured to operably connect the assembly to the pulsegenerator and transduce the first pulsatile energy to the secondpulsatile energy, e.g., as described above. The manner in which theproximal connector operably connects to the pulse generator may vary, asdesired, where a given type of connector may be a press fit connector,latch connector, screw connector, threaded connector, magneticconnector, push-to-connect connector, Yor-lock connector, claw clampconnector, gasket connector, socket connector, flanged connector,cam-and-groove socket, quick-connect connector and the like, wherealigners or detents may be employed, as desired, to provide for aconnection that repeatably and accurately positions the proximalconnector in relation to the pressure generator and/or electricalconnectors.

As reviewed above, in some instances the conversion is fluid to fluidenergy conversion, e.g., where the first pulsatile energy is pneumaticpulsatile energy, and the second pulsatile energy is hydraulic pulsatileenergy. In such instances, the proximal connector may include a proximalchamber and a distal chamber separated by a membrane, e.g., where themembrane hermetically seals the distal chamber from the proximalchamber. The proximal chamber may be configured to receive pneumaticpulsatile energy from the pulse generator. The volume of the proximalchamber may vary, ranging in some instances from 0.1 mL to 100 mL, suchas 1 mL to 4 mL, where in some instances the proximal chamber isoccupied by a gas. In certain instances, the proximal chamber forms aminimum volume chamber while still being large enough to accommodate thevolume change required to fill a balloon. In this case, the time to fillthis minimum volume chamber to a certain pressure is minimized, whichallows the frequency of the procedure to be increased. The distalchamber is fluidically coupled to the fluidic passageway of the cathetercomponent. The volume of the distal chamber may vary, ranging in someinstances from 0.1 mL to 100 mL, such as 1 mL to 4 mL, where in someinstances the distal chamber is occupied by a liquid.

The membrane separating the proximal and distal chambers is configuredto move in response to the first pulsatile energy and, in doing so,produces a second pulsatile energy in the distal chamber of theconnector. The dimensions of the membrane may vary, where in someinstances the membrane has an area ranging from 100 mm² to 5000 mm²,such as 500 mm² to 2000 mm². The membrane may be fabricated from anyconvenient elastic (e.g., pliant) material, where in some instances thematerial has a hardness ranging from Shore 10A to Shore 90A, such asShore 50A, and a thickness between 0.5 mm to 5 mm, such as 1.0 mm to 2.5mm. Examples of suitable membrane materials include, but are not limitedto: silicone, rubber, and the like and in some cases may be strengthenedby adding a reinforcing component, such as a braid. Where desired, abiasing component, such as a spring, may be provided to provide for adefault or baseline membrane position. For example, a spring may beprovided on the distal chamber side of the membrane which urges themembrane back to an initial position when force is removed from theproximal chamber side of the membrane.

While the form of proximal connectors of such embodiments may vary, insome instances the proximal chamber is defined by a proximal flange andthe distal chamber is defined by a distal flange, where the proximal anddistal flanges are positioned on either side of the membrane to definethe proximal and distal chambers, which may be hermetically sealed fromeach other by the separating membrane. In such instances, the proximalflange may include a proximal port normal to (e.g., axial to) theproximal flange configured to receive the first pulse energy, e.g.,pneumatic pulsatile energy, generated by the pulse generator. While thedimensions of the proximal port may vary as desired, in some instancesthe port has an outer diameter ranging from 1 mm to 30 mm, such as 3 mmto 8 mm and inner diameter ranging from 1 mm to 30 mm, such as 2 mm to 7mm. In such instances where the proximal flange has a proximal port theport may have a length ranging from 1 mm to 50 mm, such as 3 mm to 10mm. In such instances, the distal flange may include a distal portfluidically coupling the distal chamber with the fluidic passage of thecatheter. While the dimensions of the distal port may vary as desired,in some instances the port has a luminal diameter ranging from 0.1 mm to10 mm, such as 1 mm to 3 mm.

In instances where the proximal chamber includes a proximal port, theproximal port is fluidically coupled to the port. In such instances, thejunction between the proximal port and the proximal chamber may includea nozzle and/or diffuser, which, in some cases, may be formedgeometrically by the proximal flange. In such instances, the nozzle ordiffuser may act to increase or decrease velocity of the flow at theexpense of fluid pressure. With such increase or decrease of velocity ofthe flow, characteristics of the energy conversion may be improved, suchas ramp up time or smoothness of energy conversion. In cases ofpneumatic flow, the speed of the gas may be high enough to inducecompressible fluid phenomena such as in sonic or supersonic flows. Insuch cases, specialized flow nozzles such as a convergent-divergentnozzle may be used to optimize flow velocity.

Where desired, the proximal connector may include one or more sensors,e.g., configured to provide data regarding one or more components of theconnector and/or the balloon catheter assembly. Any convenient type ofsensor may be included in the proximal connector, where sensors ofinterest include, but are not limited to: pressure sensors, positionalsensors, displacement sensors, proximity sensors, flow sensors,temperature sensors and the like. In some instances, the proximalconnector includes a pressure sensor operably coupled to the distalchamber. In such instances, the pressure sensor may detect pressure andchanges thereof in the liquid in the distal chamber. When included, anyconvenient type of pressure sensor may be present, where examples ofpressure sensors that may be present include, but are not limited to:resistive, capacitive, piezoelectric, optical, and MEMS-based pressuresensors, and the like. In some instances, the proximal connectorincludes a membrane positional sensor configured to provide spatial dataregarding the position of the membrane at a given time, e.g., during useof the system. When present, any convenient membrane position sensor maybe employed. In some instances, the membrane positional sensor is a Hallsensor, e.g., which may be employed in conjunction with a magnet (e.g.,permanent or electromagnet) present at a fixed location relative to themembrane, such as a fixed location of the proximal connector or thepulse generator (e.g., hand-held actuator), etc., such that the fixedmagnet is positioned to modulate voltage of the Hall Sensor uponmembrane movement. In other instances, the membrane positional sensormay be an optical sensor, electric field potential sensor, resistivesensor, magnetic sensor, angle sensor, or acceleration sensor. Further,any combination of these sensors may be used to gather positional dataof the membrane or diaphragm. In cases in which a combination ofmembrane positional sensors is employed, e.g., to ensure sensors providecorrect data across a variety of frequencies, sensor data may becombined through “sensor fusion” techniques, such as those known in theart. When present, a membrane positional sensor may be employed for avariety of different purposes, e.g., to assess vessel compliance andtreatment (such as described below), to assess proper filling of theballoon catheter assembly, to provide for a way to assess whether themembrane has been stretched beyond desired thresholds, etc. Fabricationmethods of the membrane sensor may include, but are not limited to:adhesives, direct printing, welding, embedding and the like.

Where desired, the proximal connector may further include an electricalassembly. The electrical assembly may be configured to perform a numberof functions, such as but not limited to, powering of one or moresensors, control of one or more sensors, storage of data obtained fromone or more sensors, transmission of sensor data from one or moresensors to another location, storage of information about the ballooncatheter assembly, writing and/or reading data and the like. Theelectrical assembly may vary, and in some instances may includecircuitry and/or memory. When present, the memory may store a variety ofdifferent types of information, including but not limited to:information about the balloon catheter assembly and/or componentsthereof, e.g., the distal balloon, e.g., expiration date, batch number,balloon size (e.g., balloon diameter and length), balloon rated burstand nominal pressure, cycle limit (e.g., number of allowable cycles theballoon is rated for), and cycles used for, allowable pulse frequency orduration, previous use, balloon reference pressure-volume curve, and/orindication for use, etc. The electrical assembly, when present, mayfurther include a connector, e.g., for operably connecting theelectrical assembly to the pulse generator. The electrical assembly maybe present in any convenient configuration, such as a printed circuitboard, including a flexible printed circuit board. In some cases, thesensors may transmit data wirelessly, such as through Bluetooth RF.

The various components of the proximal connector, e.g., as describedabove, may be present in a housing or over-mold, e.g., configured toprotect the proximal connector components e.g., during an accidentalfall or during packaging. The housing, if present, may be fabricatedfrom a suitably rigid material, e.g., polymeric material, and may betransparent or opaque, as desired.

As summarized above, the balloon catheter assembly may include acatheter component positioned between the proximal connector and thedistal balloon. The catheter component is configured to propagate orconvey the second pulsatile energy from the proximal connector to thedistal balloon, e.g., with minimal, if any, attenuation, such asdescribed above. The catheter component includes a portion, e.g., ashaft, that is configured to be employed as a catheter, such that it maybe introduced into a lumen of a human or another animal, e.g., mammal.While the dimensions of this portion may vary, in some instances thiscatheter portion has an outer diameter (OD) ranging from 1.50 mm to 2.50mm, such as 1.75 mm to 2.20 mm.

While the structure of the catheter component may vary, in someinstances the catheter component includes a proximal flexible tube; adistal catheter shaft (which is the catheter portion, e.g., as describedabove); and a connector connecting the distal end of the proximalflexible tube to the proximal end of the distal catheter shaft. Theproximal flexible tube is made of a pliant material, e.g., braided orunbraided polyvinyl chloride (PVC), silicone, polycarbonate (PC), andthe like, where the dimensions of the tube may vary. In some instances,the flexible tube has an inner lumen with a diameter ranging from 0.1 mmto 10 mm, such as 1 mm to 3 mm, and a wall thickness ranging from 0.1 mmto 5 mm, such as 0.5 mm to 2 mm. The length of the proximal flexibletube may also vary, ranging in some instances from 1 cm to 100 cm, suchas 5 cm to 20 cm.

The distal catheter shaft may also vary. The distal catheter shaft maybe fabricated from any suitable physiologically acceptable material,including but not limited to a polyimide, such as a polyimide braid, ora polyimide-type material and the like. In some instances, the distalcatheter shaft has a length ranging from 10 cm to 1 m, such as 100 cm to300 cm. The outer diameter of the distal catheter shaft may also vary,in some instances ranging from 1.50 to 2.50, such as 1.75 mm to 2.20 mm.The distal catheter shaft may include a first liquid passageway lumen,where the dimensions of this first liquid passageway lumen may vary. Insome instances, the diameter of this first liquid passageway lumenranges from 1.3 to 2.2 mm, such as 1.6 to 2.1 mm. The first liquidpassageway may include on or more openings at the distal end forestablishing liquid communication between the interior of the liquidpassageway lumen and the interior of the distal balloon. The one or moreopenings, when present, are configured so as to not substantiallyattenuate, and in some instances, not attenuate at all, the secondpulsatile energy as it enters the balloon from the liquid passageway. Insome instances, these openings may be configured to be a nozzle and/ordiffuser. In such instances, the nozzle or diffuser may act to increaseor decrease velocity of the flow at the expense of fluid pressure. Withsuch increase or decrease of velocity of the flow, characteristics ofthe balloon expansion may be altered, such as ramp up time, impact,force, and the like. The distal catheter shaft may also include a secondguidewire lumen. When present, the dimensions of this second guidewirelumen may vary, where in some instances the diameter of the guidewirelumen ranges from 0.25 to 0.5 mm, such as 0.37 to 0.42 mm.

Also present in the catheter component of these embodiments is aconnector connecting the distal end of the proximal flexible tube to theproximal end of the distal catheter shaft. The connector may vary asdesired. In some instances, the connector includes a first branchconfigured to provide guidewire access to a guidewire channel of thecatheter shaft and a second branch configured to fluidically couple thelumen of the proximal flexible tube and liquid passageway lumen of thedistal catheter shaft. An example of a suitable connector is a Yconnector.

In some embodiments, a fluidic passage of a catheter is configured toreceive energy transduced from one or more connectors. For example, asingle fluidic passage of a catheter may be configured to receive energyfrom two or more proximal connectors, each operably connected to thesingle fluidic passage, such that the fluidic passage receives pulseenergy transduced by each connector. In another example, a fluidicpassage of a catheter may be configured to receive energy from each of aconnector that is a barrel syringe connector (i.e., a connector that isconfigured substantially as a barrel syringe, such as a barrel syringeconnector comprising a pneumatic input port, a fluid output port, aplunger (i.e., a piston), a pneumatic chamber and a fluid chamber) aswell as another proximal connector, as described herein. In such anembodiment, the barrel syringe and proximal connector may be configuredto work synchronously to prime the fluidic passage and generatepulsatile energy. In such embodiment, the barrel syringe may be used toprime the system, i.e., apply a baseline pressure to fluid present inthe fluidic passage, and the proximal connector is subsequently used toprovide pulsatile energy to the fluid present in the fluidic passage atthe baseline pressure. In embodiments, a fluidic passage may beconnected to one or more connectors, such as one, two, three, four,five, six, seven, eight, nine, ten, 20, 50 or 100 or more connectors.Such connectors, each connected to a single fluidic passage, may be ofthe same type (e.g., proximal connectors, as described herein) and/orconfiguration or may differ in any relevant respect. Multiple connectorsattached to a single fluidic passage may be synchronized or otherwiseconfigured to transduce energy to the fluidic passage in any convenientmanner. In other cases, the output of a single connector may be operablyconnected to a plurality of fluidic passages. For example, in anembodiment, the output of a single proximal connector may be operablyconnected to multiple fluidic passages, such that the proximal connectormay be used to transmit pulse energy to each of the plurality of fluidicpassages. In another exemplary embodiment, the output of a single barrelsyringe connector may be operably connected to multiple fluidicpassages, such that the barrel syringe connector may be used to primefluid present in each of the plurality of fluidic passages. That is, thebarrel syringe connector may be configured to apply a baseline pressureto fluid present in each of the plurality of fluidic passages, andbecause one barrel syringe is operably connected to multiple fluidicpassages, each of the fluidic passages is primed simultaneously. Inembodiments, a connector may be operably connected to multiple fluidicpassages of a single catheter or more than one catheter. Further detailsregarding embodiments comprising a barrel syringe are described in U.S.application Ser. No.______ filed on event date herewith (Attorney DocketNo. AVSI-004PRV); the disclosure of which is incorporated herein byreference.

As described above, barrel syringe connectors of interest may include apneumatic input port, a fluid output port, a plunger, a pneumaticchamber and a fluid chamber. In certain instances, the plunger (i.e.,piston) of the barrel syringe may be connected to a biasing spring,which would enable the quick return of the piston to its original state.In this condition, some or all the fluid volume would be removed from afluidly coupled distal balloon. In other embodiments, a barrelsyringe-type connector is selectively connected to a vacuum (i.e., theproximal side of the connector), which would facilitate evacuation ofthe proximal side of the barrel syringe, such that the piston of thebarrel syringe-type connector would return to an original position,i.e., an equilibrium position. In embodiments of such connectors, afluidly coupled distal balloon positioned at a distal region of thecatheter could be inflated or deflated rapidly. Embodiments of suchconnectors could have a variety of sensors monitoring the state of theconnector and distal balloon fluidically coupled thereto, such aspressure sensors, volume sensors or the like.

As reviewed above, the balloon catheter assembly further includes adistal balloon. Any convenient balloon may be employed. Suitableballoons include, but are not limited to, standard angioplasty balloons,such as compliant and non-compliant angioplasty balloons. In oneembodiment, the balloon is a composite balloon that includes twodistinct layers, which layers include a non-compliant layer andcompliant layer. To describe the improvements of the current compositeballoon structure over the prior art, the two layers of the compositeballoon as individual units will be described. Non-compliant angioplastyballoons are commonly used, and, in some cases, semi-compliant balloonsare used, in percutaneous procedures because the set diameter of theballoon distributes its force equally to the surrounding vessel withoutbulging into the less stiff, healthy tissue surrounding a stenosis. Whenthe non-compliant balloon material is pressurized, the balloon firstfills, which yields a low pressure and high stretch state. When thenon-compliant balloon reaches its nominal diameter, balloon pressureincreases significantly for a correspondingly low stretch. When pressureis released in the balloon, the balloon remains at its nominal stretchbecause of the lack of elasticity in the balloon. This lack ofelasticity is problematic for three reasons: (1) unless vacuum isgenerated, a de-pressurized balloon can remain filled, which can occludeblood flow, (2) it can lead to difficulty in removing the ballooncatheter through the sheath after treatment, and (3) during pulsatiletreatment, the balloon does not force fluid out during the low-pressurephase, which prevents the required stress relaxation in the surroundingtissues. Therefore, non-compliant balloons are useful at high pressuresbut have limitations at lower pressures. Compliant angioplasty balloonstypically have a linear pressure-stretch curve. The use of theseballoons is limited in percutaneous procedures because the balloonstretches non-uniformly around hardened segments of an artery, which maycause damage to the healthy, soft tissues surrounding the hardeneddiseased tissues. With a compliant balloon, there is typically a linearincrease in balloon pressure. Compared to non-compliant balloons,compliant balloons have a “short” initial fill region, and therefore,when the pressure in the balloon is released, the balloon returns to itsinitial stretch state without requiring additional vacuum. This returnto its initial state benefits the procedure because, upon return to theinitial stretch state, blood flow is immediately restored, and theballoon can be more easily retracted through the sheath. Further, duringpulsatile angioplasty, the compliance of the balloon serves as theimpetus for forcing fluid out of the balloon, which is required to allowthe surrounding tissue to relax with low stress during the low-pressurephases. Therefore, compliant balloons are helpful at lower pressures butare limited in their ability to treat at high pressures. Alone,non-compliant and compliant angioplasty balloons are not optimal for thevarious stages of pulsatile and standard percutaneous angioplasty.Together as a composite, though, they can meet important needs of bothtreatments. In one embodiment of the composite angioplasty balloon, anon-compliant balloon is covered with a compliant sleeve to achieve an“arrowed” pressure-stretch, e.g., as further described in pending PCTapplication serial no. PCT/US2020/055458; the disclosure of which isherein incorporated by reference. The compliant layer may be a rubber,silicone, polyurethane, or nitinol material or another material that canstretch up to 100-500% before failure, can withstand thousands of cyclesbefore failure, and encounters minimal, if any, plastic deformationduring expansion. During use, the exemplary composite balloon follows anarrowed response. During the low-pressure phase, the compliant materialdominates the response. The composite balloon follows the compliantmaterial curve until the balloon stretch intersects with thenon-compliant balloon stretch. At this intersection and higherpressures, the non-compliant material dominates the balloon response.Immediately upon pressure release, the balloon returns along the arrowedresponse to the initial, or zero, stretch state. This exemplarycomposite balloon has the low-pressure benefits of compliant angioplastyballoons and the high-pressure benefits of non-compliant angioplastyballoons. Other benefits include self-folding and deflating of theballoon, tear and pin-hole mitigation, increased oscillation frequencyduring pulsatile angioplasty, and increased pushability of the balloonwhile crossing a lesion. Further details regarding composite angioplastyballoons finding use in embodiments of the invention may be found inpending PCT application serial no. PCT/US2020/055458; the disclosure ofwhich is herein incorporated by reference.

The balloon catheter assembly may or may not be a “sealed” component. Insome instances, the balloon catheter assembly is not sealed, such that afluid, e.g., liquid, may be introduced into the liquid passageway(s) ofthe assembly at the time of use and/or gas may be removed from theassembly (e.g., via de-bubbling). In yet other instances, the ballooncatheter assembly is a sealed or closed assembly, such that the liquidpassageways and balloon are pre-filled with a liquid prior to use, andthe liquid is sealed in the assembly. In either instance, the liquidthat is introduced into the lumen(s) and balloon of the assembly mayvary, where in some instances the liquid is saline. Where desired, theliquid may include a suitable contrast agent, where examples of contrastagents include, but are not limited to radiocontrast agents, such as butnot limited to, iodine contrast agents, barium contrast agents, etc.

In some instances, the above embodiments may be configured such that theprocedure may be performed completely autonomously and/or remotely. Inthese cases, the balloon catheter may be inserted into the patientmanually or using a robotic catheterization system (as described inpublished application WO 2010/025338, the disclosure of which is hereinincorporated by reference). With this system, equipment such asguidewires and balloon catheter can be advanced to the site of thelesion, and, once at the lesion, the balloon may be inflated ordeflated. With the embodiments described above, the balloon may bepre-filled with fluid so that the user does not have to fill the balloonprior to pressurization. In other instances, the composite balloonembodiment may be used to ensure that the balloon deflates and wrapspost-procedure so it may be easily removed. In such instances, theoperator may be situated at a console to control the procedure includingthe pressure, frequency, and/or duty cycle. At the same time, theoperator may be able see X-ray imaging at the same time to visualize theinflated balloon and procedural efficacy. In some instances, feedback,e.g., visual, audio, feel and the like, may be provided to the operatorto indicate procedural characteristics such as volume and/or pressurechange in the balloon, frequency, duty cycle, balloon expansion, balloonposition and the like.

The balloon catheter assembly may be configured for single or one-timeuse, such that it is disposable. Prior to use, the balloon catheterassembly may be sterile, as desired.

Various aspects of the invention being generally described above,elements of the invention are now further reviewed in the context ofspecific embodiments.

Specific Embodiment

A system in accordance with embodiment of the invention for generatinghigh frequency angioplasty balloon oscillations is schematicallyillustrated in FIG. 1. In some instances, the system can include a pulsegenerator which has a potential energy source, such as a high voltage orpressure source, a switching system, e.g., for controlling the highpotential source, etc., and a balloon catheter assembly for convertingthe output of the pulse generator (i.e., first pulsatile energy), intohydraulic oscillations (i.e., second pulsatile energy) of an angioplastyballoon. In embodiments, the potential energy source acts to drive theballoon angioplasty oscillations, a switching system controls thefrequency, duty cycle, and/or amplitude of the outputted energy from thepulse generator, a proximal connector of the balloon catheter assemblyconverts the outputted energy into hydraulic oscillations that therebygenerate oscillations in an angioplasty balloon catheter, and the highflow balloon catheter allows the pressure oscillation inputs to thesystem to be achieved and optimized at the balloon output. Variations ofthis system are provided in each of the embodiments below. The followingembodiments are not meant to be an exhaustive list but are meant toprovide examples of various configurations of the overall system.

In some embodiments as illustrated schematically in FIG. 1, the systemincludes two components: a pulse generator 70 (to the left of the dashedline), which may be configured to be reusable; and a balloon catheterassembly 1 (to the right of the of the dashed line), which may beconfigured to be used a single time (e.g., such that it is disposable).The terms “reusable” and “disposable” as employed here and elsewherethroughout the description are used for convenience in describing anembodiment of the invention illustrated in FIG. 1. However, theinvention is not so limited. As such, any part of the device may beconfigured for one time use or for use multiple times, as desired. Inthe embodiment illustrated in FIG. 1, the pulse generator 70 includesthe potential source 870, a potential regulator 880, and a controller72. The pulse generator also includes a switch or oscillator (such as asolenoid) 14, which may be a present in a hand-held component oractuator of the pulse generator, as desired. Also illustrated is theballoon catheter assembly 1 which includes a proximal connector 400 thatincludes a membrane 30, a pressure and/or flow transducer 31, anelectrical connector 13, a high-flow catheter 16 and balloon 2. Inputsto the pulse generator 70 can include feedback from sensors, such as apressure or flow transducer 31 or from user inputs such as buttons orswitches. The output from the pulse generator 70 may include power,logic, and/or regulated 880 or un-regulated potential energy 870, suchas that from high-pressure fluid or voltage in the form of firstpulsatile energy and is transmitted to the balloon catheter assembly 1.The balloon catheter assembly 1 converts the first pulsatile energyoutput to hydraulic oscillations in the fluid communication path 35,which are output to the high-flow catheter 16 and balloon 2.

FIG. 2 provides an illustration of a balloon catheter assembly 200according to an embodiment of the invention, e.g., that may be used in asystem as schematically illustrated in FIG. 1. Balloon catheter assembly200 includes proximal connector 210 having a proximal port 212 foroperably connecting to a pneumatic output of a pulse generator (notshown), a proximal flexible tube 220 coupled to a distal port 214 of theproximal connector; a distal catheter shaft 240 having an angioplastyballoon, such as a composite balloon 250 located at a distal endthereof; and a Y-connector 230 connecting the distal end of the proximalflexible tube 220 to the proximal end of the distal catheter shaft 240.Also shown is optional valve 260 positioned between the distal end ofthe proximal flexible tube 220 and the Y-connector 230. When present,the proximal flexible tube 220 acts a strain relief between the proximalconnector 210 and the Y-connector 230, distal catheter shaft 240, andangioplasty balloon 250. When present, valve 260 may be employed tointroduce fluid into the liquid passageways of the balloon catheterassembly. In some instances, valve 260 is not present. For example, asdescribed above, the balloon catheter assembly may be a closed or sealedsystem that is provided to a user prefilled, e.g., with a suitablecontrast agent containing liquid. In such instances, the valve 260 maynot be provided since fluid priming is not required to use the assemblyin the system of the invention.

FIGS. 3A to 3D provide different views of a proximal connector of aballoon catheter assembly in accordance with embodiments of theinvention. FIG. 3A provides a cutaway side illustration of proximalconnector 300. Proximal connector 300 includes proximal flange 310 anddistal flange 350 separated by membrane 330. Proximal flange 310 definesproximal chamber 315 which is accessed by proximal port 320. Distalflange 350 defines distal chamber 355 which is accessed by distal port360. Pressure transducer 325 is operably coupled to distal port 360 anddistal chamber 355. The proximal and distal flanges 310,350 are heldtogether by screws, as illustrated by screw 370. Alternatively, theflanges can be fixed via any other appropriate assembly method such asan adhesive, weld, or other means. In other instances, the flanges canbe fabricated as a single component via a multi-stage injection moldingor over-molding process around the flexible membrane and electronics.Also shown is Hall sensor 335, permanent magnet 448 (which may also belocated in the handheld actuator 400, electrical connector 390, andflexible printed circuit board 397. The threaded portion 398 at thedistal end of the distal port serves as the interface between theproximal flexible tube and the distal flange. FIG. 3B provides an endview of proximal flange 310 of proximal connector 300. As seen in FIG.3B, screws 370 are positioned circumferentially around the flange toprovide connection to the distal flange (not shown). Also shown isproximal port 320 and electrical connector 390, which provides foroperable electrical connection to the pulse generator (not shown). FIG.3C shows an outer side view of the proximal connector 300, showing theproximal and distal flanges 310,350 joined together by screws 370. Alsoshown is memory 395, which is electrically coupled to a flexible printedcircuit board 397 which is electrically coupled to electrical connector390. Similarly, pressure sensor 325 is electrically coupled to theflexible printed circuit board 397. FIG. 3D shows a perspective view ofproximal connector 300. FIG. 3E provides a view of the proximalconnector 300 with over-mold 380 which is fabricated from a rigid,opaque material that serves to protect the various components, e.g.,circuitry, sensors, etc., of the proximal connector. The proximalconnector may have diameter and width variations to accommodatedifferent balloon types while still being able to be connected to acommon hand-held actuator. For example, for peripheral or coronaryballoons, the proximal connector may have dimensions to accommodate avolume change between 1-20 ml. For larger balloons such as valvuloplastyballoons, the proximal connector can be enlarged to accommodate a volumechange up to 50 mL-100 mL.

The flexible printed circuit board, 397, which connects various sensorson the assembly to the proximal flange to allow connection to thehandle, regardless of the size of the proximal connector, is furtherillustrated in FIGS. 3F to 3H, which provide front, back, and isometricviews of flexible printed circuit board 397. This embodiment allows forthe size of the proximal connector to change (e.g., as described above)with only an increase in length of the flexible PCB and not a completeredesign of the electronics. L_(Prox) of the flexible printed circuitboard is the length required between the electrical connector 390 andthe bend to the diaphragm for the Hall sensor 335. L_(Distal) is thelength from the electrical connector 390 to the pressure transducer 325.These two lengths can be adjusted to accommodate changes in the size ofthe proximal connector. Also shown is memory 395.

FIGS. 4A to 4C provide different views of a hand-held component, whichmay be referred to as an actuator, of pulse generator according toembodiments of the invention. FIG. 4A provides a side view of hand-heldactuator 400, which is configured to be held in a hand of an adult humanand includes a gripping region 410, a distal connector 420, proximalstrain relief region 405, pulse generator connector 406, and actuatorbutton 430. Gripping region 410 may be configured to be easily grippedby adjusting the geometry to fit the human hand, by using a soft plastic(e.g., rubber, silicone, thermoplastic elastomer (TPE)) over-mold, orthe like.

FIG. 4B provides an end on view of the connector 420 of actuator 400. Asseen in FIG. 4B, connector 420 includes electrical connector 430 andpneumatic connector 440 for establishing connection with the proximalport of the proximal connector (not shown). The connector 420 alsoincludes a detent to ensure appropriate, reliable, and repeatableconnection of the proximal connector. To release the proximal port ofthe proximal connector 300 from the pneumatic connector 440, a releaseplate 445 with release buttons 446 may be used.

FIG. 4C provides a cutaway view of actuator 400. Within actuator 400, anelectromagnetic 3/2-way solenoid 470 may be used. The solenoid 470includes a pressure inlet port 471, outlet port 472, electromagneticcoil 473, valve poppet and spring assembly 474, and exhaust port 475.The actuator may have added space for an electronic passageway orprinted circuit board 485 and pneumatic passageway 486. Further, in someinstances, a permanent magnet 448 may be situated in the connector 420of the actuator 400 for inducing a voltage and/or current in the Halleffect sensor, which is attached to the membrane of the proximalconnector (not shown). This electromagnet may also be located in theproximal connector. The 3/2-way solenoid 470 operates in two states—anON and OFF state. During the ON state, the valve poppet and springassembly 474 is actuated by energizing the electromagnetic coil 473allowing high-pressure flow from the inlet 471 to proceed to the outlet472 and the proximal connector (not shown) to pressurize the balloon. Inthe OFF state, the electromagnetic coil 473 is de-energized, and thevalve poppet and spring assembly 474 is closed allowing the pressurizedfluid from the proximal connector (not shown) to be exhausted throughthe inlet 472 to the exhaust port 475. To reduce noise, a noise reducer(not shown) at the exhaust port 475 may be used. Various electricalconnectors may be used to transport signal and power to and from thepulse generator console (not shown) to the electrical contacts 430,actuator button 430, and electromagnetic coil 486 and may be located inregion 485. Pneumatic connections may be transported and connected inthe pneumatic connector region 486. FIG. 4D provides an overhead view ofactuator button 430.

Actuator button 430 may be a membrane-type switch or any similar type ofbutton configuration, such as known in the art. The switch may byimpenetrable to liquids or cleaning solutions. In some instances, theactuator button 430 may include an ON/OFF switch 490, ON/OFF LEDconfiguration 491, control manipulator buttons 492, and controlmanipulator LEDs, 493.

FIGS. 4E and 4F provide exploded and assembled views, respectively, ofan actuator 400 coupled to a proximal end connector 300 via connector420. Electrical connector 430 may be spring loaded to account for anytolerance differences or movement generated during the repeatedconnection and disconnection of the proximal connector.

Model

A mathematical model of the oscillating system is described below. Thismodel has several purposes including for controlling the system inreal-time (e.g., for a state-space controller). The mathematical modeldescribes the system of FIG. 1 where a high potential source isconverted to fluid pressure oscillations in the catheter and to theballoon. The input oscillations may be modelled as instantaneous stepinputs of pressure, P_(input). The oscillations flow along a catheterwith radius 2 r and length/to the angioplasty balloon. The fluidresponds rapidly to the step input, but as the balloon pressurizes, thefluid pressure gradient decays to equilibrium with the input steppressure. The volume-pressure relationship of the balloon determines thecorresponding pressure generated in the balloon for a given volume andballoon stretch. After the step input, the pressure gradient is treatedas quasi-static and independent of time for small time steps. The flowthrough the lumen of the catheter is modeled using the Navier-Stokesequation for pipe flow:

$\begin{matrix}{{\rho( {\frac{\partial v_{z}}{\partial t} + {v_{r}\frac{\partial v_{z}}{\partial r}} + {\frac{v_{\theta}}{r}\frac{\partial v_{z}}{\partial\theta}} + {v_{z}\frac{\partial v_{z}}{\partial z}}} )} = {{- \frac{dP}{dz}} + {\rho G_{Z}} + {\mu\lbrack {{\frac{1}{r}{\frac{\partial}{\partial r}( {r\frac{\partial v_{z}}{\partial r}} )}} + {\frac{1}{r^{2}}\frac{\partial^{2}v_{z}}{\partial\theta^{2}}} + \frac{\partial^{2}v_{z}}{\partial z}} \rbrack}}} & (1)\end{matrix}$

where system parameters are identified in Table 1.

The tube is assumed to be rigid, resulting in unidirectional flow(v_(r)=v_(θ)=0). The contrast mixture is modeled as an incompressiblefluid, so that

${\nabla \cdot \overset{arrow}{v}} = {{\frac{\partial v_{z}}{\partial z} + \frac{\partial v_{r}}{\partial r} + \frac{\partial v_{\theta}}{\partial\theta}} = {0.}}$

Gravitational effects are neglected. The pressure gradient is treated asquasi-static for small time steps,

${\frac{\partial}{\partial t}( \frac{dP}{dz} )} = {\frac{dP}{dz}.}$

Applying these assumptions reduces equation (1) to:

$\begin{matrix}{{\rho\frac{\partial v_{z}}{\partial t}} = {{- \frac{dP}{dz}} + {\mu\lbrack {\frac{1}{r}{\frac{\partial}{\partial r}( {r\frac{\partial v_{z}}{\partial r}} )}} \rbrack}}} & (2)\end{matrix}$

TABLE I DEFINITIONS AND VALUES Symbol Quantity Units/Value P Pressure Pav Velocity m/s ρ Density 1100 kg/m³ μ Viscosity 1.3E−3 Pa*s G_(z)Acceleration due to gravity 9.81 m/s² R Outer radius of catheter shaft0.8 mm φ Dimensionless velocity — ξ Dimensionless radial position — τDimensionless time —

The dimensionless parameters include dimensionless radial position ξ:

$\begin{matrix}{{\xi = \frac{r}{R}}{v_{z} = {{{- \frac{R^{2}}{4\mu}}\frac{dP}{dz}{\varphi(\xi)}\tau} = \frac{\mu t}{\rho R^{2}}}}} & (3)\end{matrix}$

where r is a radius of the tube, the z-direction velocity v_(z) is:

$\begin{matrix}{v_{z} = {{- \frac{R^{2}}{4\mu}}\frac{dP}{dz}{\varphi(\xi)}}} & (4)\end{matrix}$

where

$\frac{dP}{dz}$

is the pressure gradient along the tube and φ(ξ) is dimensionlessvelocity along the radius of the tube, and dimensionless time is τ:

$\begin{matrix}{\tau = \frac{\mu t}{\rho R^{2}}} & (5)\end{matrix}$

Thus equation (2) becomes

$\begin{matrix}{\frac{\partial\varphi}{\partial\tau} = {4 + {\frac{1}{\xi}{\frac{\partial}{\partial\xi}( {\xi\frac{\partial\varphi}{\partial\xi}} )}}}} & (6)\end{matrix}$

Letting

φ=1−ξ²−Ψ  (6)

so that the no slip boundary condition is Ψ=1−ξ² at τ=0. Solving (3) byseparation of variables gives

$\begin{matrix}{\Psi = {\sum\limits_{n}{A_{n}e^{{- \alpha_{n}^{2}}\tau}{J_{0}( {\alpha_{n}\xi} )}}}} & (6)\end{matrix}$

where J₀ is the Bessel function of zeroth order and first type, andα_(n) are its zeros. If the fluid is initially at rest (φ=0 at τ=1),then

$\begin{matrix}{A_{n} = \frac{8}{\alpha_{\eta}^{3}{J_{1}( \alpha_{n} )}}} & (6)\end{matrix}$

The velocity profile is then defined

$\begin{matrix}{v_{z} = {\frac{1}{4\mu}\frac{dP}{dz}{R^{2}\lbrack {\xi^{2} - 1 + {8{\sum\limits_{n}{\frac{J_{0}( {\alpha_{n}\xi} )}{\alpha_{n}^{3}{J_{1}( \alpha_{n} )}}e^{{- \alpha_{n}^{2}}\tau}}}}} \rbrack}}} & (6)\end{matrix}$

and the volumetric flow rate is

Q=πR ² v _(z)  (6)

If the fluid is instead at some fully developed velocity with an averagevelocity v _(z0), then the initial condition is modified φ=v _(z) atτ=0, or Ψ=1−ξ²−v _(z,0). Now,

$\begin{matrix}{A_{n} = \frac{{2\alpha^{2}{\overset{\_}{v}}_{z0}} + 8}{\alpha_{n}^{3}{J_{1}( \alpha_{n} )}}} & (6)\end{matrix}$

For a coaxial catheter shaft, the volumetric flow rate is modified witha scale factor to account for additional frictional losses at the innerwall, where k=R_(i)/R (Papanastasiu,

$\begin{matrix}{{ 1999 ).Q} = {\pi R^{2}{{\overset{\_}{v}}_{z}\lbrack {( {1 - k^{4}} ) - \frac{( {1 - k^{2}} )^{2}}{\ln( {1/k} )}} \rbrack}}} & (6)\end{matrix}$

To use this model for real-time control or procedural planning, systemparameters are identified. System parameters of this model include stepinput characteristics, balloon dimensions, catheter construction anddimensions, pressure-volume relationship of the balloon, and the like.

Step input characteristics are system dependent and can be measured(e.g., during the manufacturing process) and built into the system.Likewise, with various sensor measurements built into the system, thesystem, in certain embodiments, may be able to measure the step inputresponse generated by the pressure generator.

In certain embodiments, balloon dimensions and catheter construction anddimensions can be pre-loaded onto the balloon catheter memory. Thesedimensions include balloon length, diameter, shape, and the like.Catheter construction and dimensions include details such as the shapeof the cross-section of the catheter lumen (e.g., co-axial,co-extrusion, etc.) and catheter length, outer diameter, inner diameter,ratio of flow channel area to guidewire channel area, and the like. Incertain embodiments, the pressure-volume relationship of the balloon canbe measured and pre-loaded onto the balloon catheter memory. An exampleof a pressure-volume relationship for an unrestrained 4 mm diameter×20mm length balloon is shown in FIG. 5.

Using these measured system characteristics and the model derived above,the system may be controlled in real time (e.g., using negative feedbackcontrol and/or feedforward control) to ensure pressure amplitude, dutycycle, and frequency are appropriately set during the procedure. Twoexamples of the experimentally measured pressure in the balloon andforce output from the balloon is shown in FIG. 6. The model, as derivedabove, predicts the experimental measurements accurately. With such apredictive model and with feedback from system measurements, proceduralcharacteristics (frequency, pressure input, and duty cycle) can beadjusted to ensure maximized treatment effect.

This pressure-volume relationship of FIG. 5 and “unconstrained balloon”of FIG. 6 represents the relationship between pressure and volume of theballoon when the balloon is not constrained by an external constraint(e.g., a hard stenosis embedded within a vessel wall). When the balloonis constrained by healthy tissue, this pressure-volume relationship isdifferent. In certain cases where the balloon is constrained, the curvehas a steeper slope (i.e., the pressure increases with a higher rate fora smaller volume of fluid). Therefore, the pressure-volume curve is casedependent and may be steeper with more diseased tissue. Because thiscurve is case dependent, the pressure-volume curve must be generated ona case-by-case basis inside the patient (i.e., in-situ) and duringtreatment. With the described embodiments of the system, both thepressure and the volume in the system can be measured in-situ withvarying inputs to the system. For example, at the beginning of theprocedure, according to the above embodiments, the pressure in theballoon may be increased to known values while the volume in the balloon(e.g., using the described positional sensor) is measured to generatethe in-situ pressure-volume curve (CYCLE 1 of FIG. 7). In certaininstances, this treatment-based pressure-volume curve may be compared tothe unconstrained pressure-volume curve, which in some cases is anindication of a successful treatment, or to curves measured during thetreatment progression (CYCLE 1000 or CYCLE 10000 of FIG. 7). Comparingthe pressure-volume curves in this way can be used to provide arepeatable measure of outcome, e.g., treatment success, insufficientballoon diameter, balloon under-expansion, and the like even duringpulsatile balloon angioplasty. In other instances, if the treatment isnot successful at a certain pressure level over the treatmentprogression (i.e., the balloon volume remains substantially the sameindicating an under-expanded balloon and non-compliant/non-treatedvessel), the system may incrementally increase the pressure within asafe range until the balloon volume increases. Alternatively, the systemmay provide feedback (audio, visual, feel, and the like) to the operatorto indicate the pressure amplitude of the pulses is not high enough. Inother instances, the system is configured to detect single-planeunder-expansion, an example of which is shown in FIG. 7B (Panels A-D).FIG. 7B (Panels A-B) show a fluoroscopy image of a focal lesion, whichis restricting blood flow. To treat the lesion, standard BA is performedby inserting the balloon across the lesion and increasing the pressurein the balloon. In one fluoroscopy plane, after increasing the pressure,the balloon expands as shown in FIG. 7B (Panel C). However, as seen inthe normal fluoroscopy image plane (FIG. 7B (Panel D)), the balloonremains under-expanded, which could be missed by the physician. With theembodiments described above, the system can measure when the balloon isunder-expanded without requiring multiple projection fluoroscopy images.This benefit reduces procedural time, radiation exposure to thephysician and patient, and injected contrast.

Measurements of Vessel Compliance

As described in detail below, vessel compliance is a measurablecharacteristic of blood vessels calculated based on a ratio of thechange in vessel volume for a given change in pressure. Vesselcompliance is an important characteristic for observation becauseimproving vessel compliance is a prerequisite to definitive treatment ofcertain underlying blood vessel disease conditions, such asatherosclerosis. Changes in vessel compliance are seen in the differentpressure-volume curves depicted in FIG. 7A, described above. In FIG. 7Athe pressure-volume, i.e., vessel compliance, characteristic of atreated vessel changes as a result of treatment from CYCLE 1 to CYCLE1000 to CYCLE 10000.

Systems according to the present invention may be configured to assessvessel compliance by obtaining measurements in-vivo of changes in volumeat different pressures (or changes in pressure) applied to vessels. FIG.7C provides an example of measurements of changes in vessel complianceobtained during treatment using a system according to the presentinvention. As described in detail below, embodiments of the presentinvention enable measurement of relative compliance change of theluminal tissue (i.e., a vessel) in real time during application of asystem of the present invention to provide pulsatile intravascularlithotripsy treatment. Systems of the present invention may beconfigured to measure, and update, treatment parameters based oncompliance change of the vessel. For instance, after calcium cracking(i.e., breaking up of CP tissue), the luminal tissue (i.e., a vessel)and balloon may expand significantly, contributing to a large gain incompliance, as measured by the system. However, after the vessel hasfully expanded, changes in compliance, as measured by the system, maysubside. Identification of such conditions may indicate that treatmentmay be halted because no further appreciable luminal gain is occurring.

Systems may be configured to measure pressure in any convenient manner.In some instances, embodiments of systems according to the presentinvention may comprise a pressure gauge as described herein formeasuring pressure in, for example, fluid passages and distal balloon ofa balloon catheter assembly, including, for example, balloon catheterassemblies according to the present invention. In some instances, apressure gauge may be installed such that it is configured to measurepressures of a distal chamber of a proximal connector, as seen, forexample, in pressure transducer 325 in FIG. 3A.

Systems may be configured to measure changes in volume of a vessel inany convenient manner. In some instances, embodiments of systemsaccording to the present invention may be configured such that changesin the position of a membrane separating proximal and distal chambers ofthe proximal connector reflect changes in volume of the distal balloon.Changes in the volume of the distal balloon reflect changes in thecross-sectional area of a vessel and therefore changes in volume of thevessel. Such embodiments may further comprise a Hall sensor and apermanent magnet for measuring changes in the position of such amembrane. A Hall sensor refers to a sensor configured to sense thepresence of, or changes in, a magnetic field, i.e., by use of the HallEffect. A permanent magnet may be comprised of any convenient magneticmaterial, or an electromagnet, as desired, such that relative changes inposition of the Hall sensor with respect to the permanent magnet aredetected by the Hall sensor. Sensors such as the Hall sensor andpermanent magnet described above may be used to measure the change involume of the distal balloon as well as the rate at which the distalballoon inflates, i.e., the rate of vessel volume change.

FIG. 8 depicts the system according to an embodiment of the presentinvention shown in FIG. 1, further configured to assess vesselcompliance according to an embodiment of the present invention. Elementsof the system shown in FIG. 8 that are identical to those shown in FIG.1 are described above in connection with FIG. 1. Hall sensor 805 ispositioned on membrane 30 such that changes in position of membrane 30relative to permanent magnet 810 positioned on proximal connector 400trigger changes in output of Hall sensor 805. Such changes in output ofHall sensor 805 are indicative of changes in volume of distal balloon 3.As described in connection with FIG. 1, pressure or flow transducer 31is configured to measure pressure applied to catheter 16 and balloon 2.Measurements of changes in volume based on Hall sensor 805 and permanentmagnet 810 and changes in pressure based on pressure gauge 31 are usedto measure vessel compliance in-vivo. Such measurements of vesselcompliance can be taken during treatment. Such measurements are used todevelop pressure-volume curves 815 showing the pressure-volumerelationship at a treatment stage. Pressure-volume curves 815 can begenerated at different stages of treatment and may be used to assesstreatment effectiveness, compare treatment across different settings orto revise or otherwise adjust treatment in order to optimize theeffectiveness of treatment. In embodiments, pressure-volume curves 815may resemble those set forth in, for example, FIG. 7A, described above,or FIG. 17, described below. The data used from these pressure volumecurves can be gathered and batched and eventually used to predict (i)success or failure of therapy, (ii) a need to adjust or attenuate energyused in future treatments of populations or similar vessels, (iii)complicating conditions, such as circumferential calcium versus 270degrees of calcium or (iv) the location of areas in the arterial anatomythat are relatively fixed or those exposed to significant torsion orflexion. While the exemplary embodiment for measuring vessel complianceaccording to the present invention is shown in FIG. 8 in the context ofthe system described in connection with FIG. 1, it is to be understoodthat the technique for measuring vessel compliance according to thepresent invention is not so limited and may be applied to otherballoon-based systems such as those indicated in 820 of FIG. 8, such as,for example, laser-based techniques, ultrasound-based techniques,pulsatile balloon-based techniques, such as those described herein, orplain balloon angioplasty-based techniques. It is also understood thatdata collected upon application of the system, e.g., in connection withtreatment, such as pressure-volume data as described above, may be usedto apply various algorithms for machine learning. Such machine learningapplications may be trained to make predictions such as those describedabove, e.g., regarding the success or failure of a treatment, a need tochange aspects of the treatment, such as energy applied, the presence ofcomplicating conditions or aspects of the underlying anatomy of asubject or population of subjects. Any convenient machine learningalgorithm or technique or model may be applied, for example algorithmsor techniques that apply supervised learning, unsupervised learning,semi-supervised learning, reinforcement learning or dimensionalityreduction. In embodiments, machine learning techniques of interest mayinclude artificial neural networks, including convolutional neuralnetworks or other methods of applying deep learning techniques, decisiontrees, support vector machines, regression analysis, Bayesian networksor genetic algorithms. Machine learning techniques of interest may beimplemented in software such that they can be executed on ageneral-purpose processor, such as commercially availablegeneral-purpose processors, or a special purposes processor, such asgraphics processors, such as commercially available graphics processors,or may be implemented on dedicated hardware.

FIG. 9A depicts an isometric view of proximal connector 900 according toan embodiment of the present invention configured for measuring vesselcompliance, and FIG. 9B depicts a cutaway view of proximal connector900. Proximal connector 900 includes proximal flange 910 and distalflange 915 separated by membrane 920. Proximal flange 910 definesproximal chamber 925 which is accessed by proximal port 930. Distalflange 915 defines a distal chamber 935 which is accessed by distal port940. Pressure transducer 945 is operably coupled to distal port 940 anddistal chamber 935 defined by distal flange 915. Pressure transducer 945is configured to observe changes in pressure applied to a distal balloonconnected via distal flange 915. Permanent magnet 950 is connected toproximal flange 910 and is configured to remain in a fixed positionrelative movement of membrane 920. Hall sensor 955 affixed to membrane920 is configured to move with membrane 920 relative to permanent magnet950 enabling observation and measurement of changes in volume of adistal balloon.

Distance 955 represents the furthest left position (X_(l)) that membrane920 can travel within proximal chamber 925. Distance 960 represents thefurthest right position (4) that membrane 920 can travel within distalchamber 935. Distance 960 represents the position (x) of membrane 920depicted in FIG. 9B. Hall sensor 955 and permanent magnet 950 areconfigured to sense changes in membrane 920 position between leftmostdistance 955 and rightmost position 960.

FIG. 10 depicts a plot 1005 of the calculated, i.e., analytical, outputof a Hall sensor affixed to a membrane, such as the configuration ofHall sensor 955 and permanent magnet 950 in the schematic shown in FIGS.9A and 9B, and a plot 1010 of experimental results confirming theanalytical results of plot 1005. The analytical calculation for themagnetic flux density, B, i.e., the magnitude of the effect of themagnetic field, along the symmetry axis of a permanent, axiallymagnetized ring magnet such as in the configuration of permanent magnet950 in the schematic shown in FIGS. 9A and 9B is:

$B = {\frac{B_{r}}{2}\lbrack {\frac{D + z}{\sqrt{R_{a}^{2} + ( {D + z} )^{2}}} - \frac{z}{\sqrt{R_{a}^{2} + z^{2}}} - ( {\frac{D + z}{\sqrt{R_{i}^{2} + ( {D + z} )^{2}}} - \frac{z}{\sqrt{R_{i}^{2} + z^{2}}}} )} \rbrack}$

where B_(r) is the remanence field of the magnet independent of themagnet's geometry, z is the distance from a pole face on the magnet'saxis, D is the thickness of the ring, R_(a) is the outside radius of thering, and R_(i) is the inside radius of the ring. The magnitude of themagnetic flux density induces a measurable voltage change in the HallEffect sensor depending on the distance, z, of the Hall effect sensorfrom the permanent magnet.

The x-axis 1015 of plot 1005 indicates distance of a membrane from areference position (i.e., position of a permanent magnet), such asmembrane distances 955, 960 and 965 in FIG. 9B. The y-axis 1020 of plot1005 relates to the magnetic flux density, i.e., the magnitude of theeffect of the magnetic field, associated with a permanent magnet atdifferent distances from the permanent magnet. Plot 1005 depicts theleftmost possible membrane position at position 1025, and the rightmostpossible membrane position at position 1030 (where “right” and “left”refer to membrane positions seen in FIG. 9B, described above).Analytical results of the effect of the magnetic field versus distancefrom the permanent magnet are shown on curve 1035. Curve 1035 indicatesthat effects of the magnetic field vary over the operable range of themembrane, in particular, between position 1025 and position 1030,providing confirmation that a Hall sensor, such as, for example, theconfiguration of membrane-mounted Hall sensor and permanent magnet shownin FIGS. 9A and 9B, is a feasible solution to measure membrane positionand therefore volume of the distal balloon (and therefore changes invessel volume).

The x-axis 1037 of plot 1010 represents changes in volume of a distalballoon based on different membrane positions. The y-axis 1040 of plot1010 represents voltage levels generated by a Hall sensor as the Hallsensor travels different distances from a permanent magnet. Curve 1045reflects voltage data collected from a Hall sensor such as, for example,the configuration of membrane-mounted Hall sensor and permanent magnetshown in FIGS. 9A and 9B. Curve 1045 indicates a different voltage valuefor each balloon volume value shown on x-axis 1037 (associated withdifferent membrane positions or distances between the membrane and apermanent magnet). That is, each membrane position, and thereforeballoon volume, results in a different voltage level generated by theHall sensor. That is, the function represented by curve 1045 provides aunique solution such that each voltage corresponds to a differentmembrane position (diaphragm distance from the permanent magnet), whichrelates to balloon volume. The largest change in measured voltage(plotted on y-axis 1040 of plot 1010) occurs between volume displacementmeasurements of approximately 0 mL and approximately 2.75 mL, allowingfor precise volume measurements through an operating region of interest,i.e., balloon volumes between 0 mL and 2.75 mL. These results provideconfirmation that a membrane-mounted Hall sensor is a feasible approachto monitoring volume changes of a distal balloon in-vivo and duringtreatment.

As described above, measurements of changes in vessel volume incombination with changes in vessel pressure can be used to assess vesselcompliance. Use of the systems and techniques described herein allow forassessment of vessel compliance in-vivo and during treatment. Changes invessel compliance, including changes during treatment or pre- andpost-treatment may be used to assess treatment efficacy and/or to adjustvessel treatment. For example, changes in vessel compliance may be usedto adjust therapeutic intensity and/or duration. Understanding andcollection of data related to treatment, such as measurements of vesselvolume and pressure, can be used for future predictive algorithms suchthat therapy is administered at varying frequencies and/or oscillationsto reduce the time necessary for treatment and to more accuratelypredict the energy required prior to administering therapy. Such aspectsof a treatment, e.g., frequency of the system and/or oscillations, maybe adjusted by the operator, or in other cases, may be automaticallyadjusted based on, for example, machine learning and/or other predictivealgorithms, as described herein.

As described in detail below, systems and techniques for measuringvessel compliance according to the present disclosure may be furtherconfigured to obtain concomitant measures of vessel volume (i.e.,absolute, in addition to relative changes in, vessel volume), such asintraarterial cross-section imaging, in order to generate absolutevessel compliance measurements. Imaging techniques such as, for example,ultrasound, cineangiography, computed tomography, intravascularultrasound (IVUS) and/or optical coherence tomography (OCT), may be usedto image treated vessels pre- and post-treatment to obtain absolutevessel compliance measurements. Such measurements of absolute vesselcompliance may be compared across treatment groups.

While FIGS. 8, 9A, 9B and 10 depict configurations for measuring vesselcompliance in connection with pulsatile balloon catheter systems inaccordance with the present invention, such presentation is forillustrative purposes only and disclosure is not limited to suchembodiments. It is to be understood that the techniques described formeasuring vessel compliance, including in-vivo measurements duringtreatment by, for example, measuring volume by using a Hall sensor andpermanent magnet in conjunction with a pressure gauge, may also beapplied to other balloon-based systems and methods, such as otherballoon-based systems and methods of treating diseased vessels.

Measurements During Treatment for System Control

Balloon angioplasty systems, such as, for example, pulsatile ballooncatheter systems according to the present invention, may benefit frombeing configured to monitor for safe and effective operation of thesystem. Systems according to the present invention may be configured tomonitor one or more measurable characteristics to ensure safe andeffective operation and treatment. For example, in some embodiments ofsystems of the invention, an output pulse of energy should correspond toan expected value, such as an input pulse of energy or a thresholdamplitude of an energy pulse. Such embodiments may be configured tomeasure, or to compare, or to otherwise monitor, output pulses of energyto ensure compliance. In other embodiments of systems of the invention,the input pressure applied to the system should correspond to the peakpressure measured in the system. In still other embodiments, the inputpressure applied to a catheter component should correspond to a targetthreshold pressure. By “correspond to” an expected value, it is meant,in some cases, that the measured value is greater than the expectedvalue or, in other cases, that the measured value is less than theexpected value, in each case depending on the configuration of thesystem. In another example, in some embodiments of systems of theinvention the input pressure applied to the system should correspond toa minimum, or maximum, or acceptable range of, changes in volume of thedistal balloon.

More generally, systems according to the present invention may beconfigured to detect system states. System states may refer to a normaloperation state of the system or a fault operation state. A faultoperation may mean the system is in any undesired system state, such asan unexpected pressure drop or a system leak or a balloon burst or anyother unsafe or ineffective state.

This aspect of the present invention relates to a simple, effective, andfast technique for detecting system states, as described above, andproviding an alarm signal indicating such system fault. In addition,this aspect of the system can also be used to predict what amount ofoscillation or energy is needed rapidly after the earliest data iscollected on compliance. In pulsatile balloon catheter systems, systemstates may be determined by configuring the system to compare a measuredcharacteristic of the system, e.g., catheter pressure, such as peakcatheter pressure, or distal balloon volume, to an expected threshold,i.e., target pressure or target volume, or minimum or maximum expectedvalues thereof. Catheter pressure may be measured using any convenientpressure sensor, such as, for example, a pressure gauge, as describedabove. In some cases, a pressure sensor may be integrated into a distalchamber of a proximal connector of an embodiment of a system accordingto the present invention. In such cases, the pressure sensor may beconfigured to measure pressure applied to a distal balloon, by, forexample, measuring fluid pressure in the distal chamber in fluidiccommunication with a distal balloon. Distal balloon volume may bemeasured using any convenient sensor, such as, for example, a membranepositional sensor or displacement sensor or other sensor, such as thosedescribed herein, configured to measure changes in volume of the distalballoon. In some cases, the membrane positional sensor is a Hall sensorand a magnet present at a fixed location of the membrane of the proximalconnector configured to measure changes in volume corresponding to thedistal balloon, as described above.

In embodiments, an electronic circuit may be configured to determinesystem states. In such embodiments, a sensor configured to measure asystem characteristic, such as those described herein, may be furtherconfigured to output an electronic signal based on the measuredcharacteristic. A person of skill in the art will understand that anydesired, measurable system characteristics may be measured by anappropriately configured sensor. In embodiments, a sensor configured tomeasure a system characteristic, such as a pressure sensor configured tomeasure system pressure or a membrane positional sensor configured tomeasure distal balloon volume, may be further configured to output anelectronic signal based on the measured characteristic, such as measuredpressure or measured volume. Such electronic signal may vary based onthe output of the sensor, i.e., the measured system characteristic, forexample, the amount of pressure measured by a pressure sensor or thevolume of the distal balloon measured by the membrane positional sensor.The electronic signal corresponding to the measured systemcharacteristic may be a digital signal or an analog signal. When thesignal is an analog signal, its voltage or current, or any othercharacteristic of the signal, such as a frequency, may vary based ondifferent measurements observed by the sensor. The electronic circuitmay be configured to compare the measured system characteristic, such asthe measured pressure signal or measured volume signal, to a targetpressure or target volume (i.e., a minimum or maximum or acceptablerange of the system characteristic) in any convenient manner. Forexample, the measured signal may be compared to a target threshold, suchas a target pressure or target volume, using a comparator circuit tocompare the measured system characteristic to a reference voltagecorresponding to a target threshold. Any convenient comparator circuitcapable of comparing the difference between characteristics of signals,such as comparing signal voltage or current, and producing a digital(i.e., binary) output indicating the result of the comparison, e.g.,which signal is larger, may be applied. In some cases, the comparatorcircuit may be an analog comparator circuit, such as a differentialamplifier, for example, a high-gain differential amplifier. In othercases, the comparator circuit may be a digital circuit, such as an addercircuit or a more complex or more specialized digital logic circuit.

In some cases, the signal corresponding to the measured systemcharacteristic, such as a measured pressure or a measured volume, may beinverted and summed with a signal corresponding to a target value orthreshold, such as a target pressure or target volume. The result of thesummation may then be applied to a comparator circuit for comparisonagainst a threshold where the threshold represents a tolerance orexpected difference between the measured system characteristic and atarget threshold (e.g., measured pressure and a target pressure ormeasured volume and a target volume). Such a configuration, where thedifference between the measured system characteristic and a target valueof the system characteristic (e.g., measured pressure and a targetpressure or measured volume and a target volume) is compared to athreshold, may allow for a buffer around the expected systemcharacteristic, which in some cases, may account for noise or othersignals that are not representative of system state.

In embodiments, the result of the comparator circuit may be (or in somecases may be converted to) a digital signal, where the logical value ofthe digital signal indicates whether the measured system characteristic(such as measured pressure or measured volume) is an expected orunexpected reading. For example, the circuit may be configured such thatthe comparator produces a digital high signal, i.e., a logical 1, whenthe measured system characteristic (e.g., measured pressure or measuredvolume) falls outside of an expected range and a digital low signal,i.e., a logical 0, when the measured system characteristic falls withinan expected range. Such digital signal may be stored in a memory. Anyconvenient electronic circuit capable of storing a digital logic signalmay be applied. In some cases, the memory may consist of a flip-flopcircuit, for example a flip-flop capable of storing a single bit. Insuch instances, the output value of the flip-flop reflects system state.For example, the output of the flip-flop may indicate a logical 0 whenthe system state is normal and a logical 1 when the system state is in afault state. Such an output of the flip-flop may be treated as an alarmsignal such that when the alarm signal is raised, continued use of thesystem may be unsafe or ineffective. Such signal may be conveyed to anoperator of the system in any convenient manner. For example, in somecases, system state may be conveyed to the operator through a warningsignal such as a warning light or sound or vibration. In other cases,system state may cause the system to automatically take an action, suchas automatically turning off aspects of the system.

In certain embodiments, it may be desirable for the system state valuestored in memory, e.g., the value stored in the flip-flop, to reflect acomparison of the maximum or minimum of the measured systemcharacteristic, such as a comparison of the measured pressure at peakamplitude of the measured pressure or a comparison of the measureddistal balloon volume at peak amplitude of the measured volume. That is,in embodiments, the system state reflects peak catheter pressure or peakdistal balloon volume. This digital data can be used for understandingpopulation and anatomic variables and the pressures and energy needed aswell as in connection with machine learning techniques, such as, forexample, training data for machine learning models, to predict theenergy needed and best therapeutic energy to apply. In such embodiments,system state may reflect whether the peak measurement of a systemcharacteristic rises to or above a target measurement value of thesystem characteristic, e.g., whether the peak amplitude of the measuredpressure or measured distal balloon volume rises to or above a targetpressure or volume, respectively, at an expected time. In suchembodiments, when the peak value of the measured characteristic fails torise to the level of an expected target value at an expected time, anunexpected pressure drop, for example, may be indicated. In someembodiments, the system may be configured to continuously monitor asystem characteristic, such as catheter pressure or distal balloonvolume, and continuously compare such measurement against target value.In such cases, in order for the output state of the flip-flop toaccurately reflect system state, the system may be configured such thatthe result of the comparator circuit is written to the flip-flop at atime corresponding to the time when the catheter is expected to beexposed to a peak measurement value, e.g., peak pressure or peak volume.That is, the flip-flop write operation is coordinated with the time thesystem is expected to exhibit a peak measurement value, e.g., peakpressure or peak volume. Any convenient technique to synchronize sensorreadings at the appropriate time may be applied. In some cases, the flipflop write operation may be synchronized by setting the flip-flop clocksignal to an inverted control signal used to control input pressure tothe catheter. In such instances, the leading edge of the flip flop clocksignal corresponds to the time that the control signal turns offpressure to the catheter, which in turn corresponds to a time thatpressure has been applied to the catheter the longest, i.e., peakcatheter pressure. Those skilled in the field will understand thatalternative configurations may be employed with similar effect, such asusing a falling-edge triggered flip-flop without inverting the pressurecontrol signal.

When configurations such as those described above for synchronizing aflip-flop write operation with a peak value of a system characteristic,such as peak system pressure or peak distal balloon volume, are applied,the system state reflected in the logical value of the memory device,i.e., flip-flop, reflects the peak value of the measured systemcharacteristic, e.g., peak pressure or peak volume. As such, systemstate may indicate that the system fails to reach a peak measurementvalue at any time during pulsatile cycle of applying and then removingpressure to the distal balloon and therefore the system is notfunctioning safely or effectively or otherwise as expected.

FIG. 11 presents a circuit diagram of an exemplary electronic circuit1102 for monitoring system state via catheter pressure according toaspects of the present invention. While the diagram shown in FIG. 11relates to measuring catheter pressure, those skilled in the field willunderstand that similar configurations may be employed to measure othersystem characteristics, such as, for example, distal balloon volume. Asseen in FIG. 11, measured pressure 1105 is an input signal to circuit1102. As described herein, the measure pressure signal may be an analogor digital signal ultimately generated by a pressure sensor attached tothe embodiment of the system and used to measure energy applied to thesystem, such as catheter pressure. Target pressure 1110 is anotherelectronic signal that is an input signal to circuit 1102. Targetpressure signal 1110 may be hardwired to a specified value or may beconfigurable based on different types of distal balloons, differenttypes of treatment strategies, including the amount of pressure expectedto be applied to the catheter. Measured pressure 1105 and targetpressure 1110 are routed to a summation circuit 1115 configured tocompute the difference between measured pressure 1105 and targetpressure 1110. That is, in the embodiment depicted in FIG. 11, summationcircuit 1115 is configured to add target pressure 1110 to a negativevalue of measured pressure 1105.

Summation result 1120 of summation circuit 1115 is compared againstthreshold value 1125. Summation result 1120 and threshold value 1125 areboth inputs to comparator circuit 1130. Threshold value 1125 is an inputsignal to circuit 1102 and may be a hardwired value or may be aconfigurable value that in either case reflects acceptable tolerancebetween measured pressure 1105 and target pressure 1110. Comparatorcircuit 1130 is configured to produce a comparator result 1135 that is adigital low value, i.e., logical 0, if the result of the comparatorcircuit 1130 is within an allowable tolerance and to produce a digitalhigh value, i.e., logical 1, if the result of the comparator circuit1130 is outside an allowable tolerance. That is, for example, in theevent measured pressure signal 1105 is unacceptably low, summationresult 1120 will, as a result, also be unacceptably low, causingcomparator result 1135 to be a digital high value or logical 1.Comparator result 1135 is connected to the data-in port of flip-flop1140, used to store system state, in this case in the form of a one-bitdigital logic value.

Solenoid trigger signal 1145 is a pressure control signal used tocontrol a solenoid that turns on pressure to a catheter. That is, whensolenoid trigger signal 1145 is high, the solenoid is controlled suchthat pressure is input into the catheter (not shown in FIG. 11) andtherefore applied to the distal balloon (not shown in FIG. 11). Whenembodiments are configured as such, pressure will have been applied tothe catheter for the longest amount of time upon the trailing edge(i.e., falling edge) of solenoid trigger signal 1145. Because thecatheter will have been exposed to pressure for the longest time uponthe trailing edge of solenoid trigger signal 1145, catheter pressure isexpected to be at its peak amplitude at that time. That is, maximumcatheter pressure is expected upon each trailing edge of solenoidtrigger signal 1145.

Prior to being routed to the flip-flop clock input signal, solenoidtrigger signal 1145 is inverted using inverter 1150. Any convenientinverter circuit or digital logic NOT gate may be applied to causeinverter output 1155 to logically reflect an inverted solenoid triggersignal 1145, such that, for example, leading edge 1170 of inverteroutput 1155 corresponds to trailing edge 1160 of solenoid trigger signal1145 and falling edge 1175 of inverter output 1155 corresponds toleading edge 1165 of solenoid trigger signal. Therefore, when flip-flop1140 is a positive-edge triggered flip-flop, i.e., it is configured suchthat the stored value is written upon each leading edge of the flip-flopclock signal, comparator result 1135 will be written to flip-flop 1140upon each trailing edge of solenoid trigger signal 1145. When comparatorresult 1135 is written at the trailing edge of solenoid trigger signal1145, comparator result 1135 reflects a comparison of measured pressure1105 at the peak amplitude of pressure applied to the distal balloonthrough the catheter.

In the embodiment shown in FIG. 11, flip-flop output signal 1180reflects system state. When the system is functioning normallyelectronic circuit 1102 is configured so that flip-flop output signal1180 is a digital low or logical 0 value meaning measured pressureappears to be within an acceptable threshold of target pressure and nounexpected pressure drop is detected. When the system is in a faultstate, electronic circuit 1102 is configured so that flip-flop outputsignal 1180 is a digital high or logical 1 value meaning measuredpressure appears to be outside an acceptable threshold of targetpressure and an unexpected pressure drop has been detected.

FIG. 12A shows results of operation of an exemplary electronic circuitused to monitor system state according to the present invention, suchas, for example, the operation of electronic circuit 1102 depicted inFIG. 11 and described above. Plot 1205 is a graph of pressure 1210,shown on the y-axis of plot 1205, over time 1215, shown on the x-axis ofplot 1205. Pressure measured in the system, i.e., catheter pressure, isshown on the plot on curve 1220. Because pressure applied to thecatheter is pulsed, i.e., is pulsatile, measured pressure 1220 forms awaveform with a peak (i.e., greatest magnitude of pressure) and a trough(i.e., least magnitude of pressure) in a periodic manner (inembodiments, the amplitude of the waveform may remain constant or canchange based on feedback from a variety of sensors or other systemfeedback or pre-programmed instructions, for example). Target pressurefor the system, i.e., the maximum expected pressure, is depicted by line1225, which shows an exemplary target pressure on plot 1205. Thethreshold for tolerable variances from target pressure 1225 is shown asthe pressure band 1230 reflecting a range of acceptable differences inpressure values from target pressure 1225. System state signal 1235reflects logical values 0 or 1, where logical value 0 indicates normaloperation of the system and logical value 1 indicates a system fault.

Plot 1205 shows normal system operation during time period 1240, betweenapproximately time 0 and 0.4 seconds. During time period 1240, peakmeasured pressures consistently rise nearly to target pressure 1225 andis consistently within the acceptable threshold 1230 of target pressure1225. Because catheter pressure is consistently within an acceptablepressure range during this time, the electronic circuit configured tomonitor system state consistently indicates normal system operation.This result is reflected in system state signal 1235 remaining atlogical 0 during time period 1240.

Also shown on plot 1205 is a period of system fault during time period1245, between approximately 0.4 seconds and 1 second. During time period1245, peak measured pressures consistently fail to rise to targetpressure 1225 and are consistently outside of the acceptable threshold1230 of target pressure 1225. Because peak catheter pressure isconsistently outside the acceptable pressure range during this time, theelectronic circuit configured to monitor system state consistentlyindicates a system fault due to the measured pressure drop. This resultis reflected in system state signal 1235 rising to and remaining atlogical 1 during time period 1245.

Catheter Burst Detection

Systems according to the present invention may be configured to detectwhether a catheter is an intact catheter, whether the catheter hascompletely failed or whether the catheter has a leak.

FIG. 12B depicts example behavior of pressure and volume measurementsfrom an intact (i.e., not leaking) catheter of a system according to thepresent invention during treatment. In FIG. 12B, the peak and troughpressures remain substantially the same throughout treatment and thevolume over the treatment does not decline.

FIG. 12C depicts example behavior of pressure and volume measurementsfrom a completely failed catheter of a system according to the presentinvention during treatment. A completely failed catheter can causedamage to the lumen and can cause damage to the amplifier assembly.Using catheter pressure and volume change, a burst catheter may bedetected within less than 0.05-2 seconds such as 0.1 seconds oftreatment. In the figure above, the volume sensor measures a drop involume, which triggers a system warning and stops the treatment. Volumedecrease may be in the range of 0.01 to 10 mL/sec such as 0.5 mL/sec.Peak pressure also decreases during the burst but lags the volumechange.

FIG. 12D depicts example behavior of pressure and volume measurementsfrom a leaking catheter of a system according to the present inventionduring treatment. A leaking catheter can cause a jet of fluid thatdamages the vessel wall. Using catheter pressure and volume change, asmeasured by an embodiment of the present invention, the leaking of thecatheter can be detected by measuring an increase in trough pressureduring the pressure cycle along with a decreasing volume in thecatheter. Trough pressure increase may be in the range between 0.1-10atm such as 1-2 atm. Volume decrease may be in the range of 0.01 to 10mL/sec such as 0.1 mL/sec. In certain embodiments, a software-basedscheme may be used to detect the combination of these conditions toimmediately shut off the system during pulsatile intravascularlithotripsy therapy.

Specific Embodiment of Barrel Connector

FIG. 13 provides a schematic of an alternative connector 1300 configuredto deliver a high-volume, low-frequency and low-pressure pulse (i.e.,pulsatile energy). Connector 1300 comprises barrel syringe 1310 withplunger (i.e., piston) 1320 separating pneumatic chamber 1330 from fluidchamber 1340. Pneumatic chamber 1330 comprises pneumatic input port1370, configured to receive energy (i.e., a first pulse energy) from themanifold assembly (not shown), e.g., in the form of pneumatic pressure,and transmit such energy to pneumatic chamber 1330. Plunger 1320 isconfigured to translate in response to pressure applied to pneumaticchamber 1330, in turn transmitting energy to fluid chamber 1340. Fluidchamber 1340 comprises fluid output port 1350 operably connected to acatheter (not shown) and configured transmit energy to catheter (i.e., afluidic chamber thereof) in response to movement of plunger 1320compressing fluid chamber 1340. Connector 1300 further comprises biasingspring 1360 configured to urge plunger 1320 to return to a startingposition when plunger 1320 is displaced.

In instances where a connector comprises an internal fluid, theconnector may be configured to receive fluid through a fluidly coupledpriming port (not shown). For example, such a fluid port may beconnected to fluid chamber 1340 in connector 1300 of FIG. 13. Throughsuch a port, a fluid such as radiopaque contrast, saline, CO₂ or thelike may be injected to prime the fluid chamber. Additionally, a vacuummay be applied to such a port so that the connector as well as thesystem as a whole can be, for example, de-gassed prior to treatment. Thepriming port may be closed and sealed so that no fluid may exit the portduring treatment.

Methods

Systems of the invention find use in a variety of applications. In someinstances, the systems find use in fracturing hardened materialsembedded within an elastic conduit. For embodiments presented herein,the present disclosure describes applications related to treatingatherosclerotic calcifications within an arterial conduit, such as acoronary or peripheral artery. However, the present system and teachingsare not solely limited to atherosclerotic calcifications nor arterialconduits and may be generally applied to other applications asdetermined by those skilled in the art. For example, this is especiallytrue for circumstances that alter arterial compliance (vesselcompliance, as described above, of an artery) or for cases that involvemedical interventions, such as the presence of a previous stent withsubsequent blockage. The compliance of the vessel is altered by theintra-luminal placement of a previous stent. Data and feedback of vesselcompliance curves can be used in connection with future therapies aswell as for prediction techniques, such as machine learning techniquesdescribed herein.

In some instances, the various embodiments of the systems describedherein are employed in methods of dynamic balloon angioplasty (DBA), atechnique that uses pressure oscillations with a generalized waveform(in some embodiments, harmonic, or frequency-specific, pressure waveformoscillations) to effectively and safely fracture calcified lesionsduring angioplasty. The concept of DBA for treating arterial calcifiedplaque is illustrated in FIGS. 14A-14E. In DBA, a catheter 16 withballoon 2 is deployed to the vessel 1400 with calcification 1450 (FIG.14B), e.g., with the assistance of a guidewire using any convenientprotocol, such as those known in the art. Through the angioplastyballoon, the plaque is subjected to high-frequency pressure oscillations(FIGS. 14C-14D). In the low-pressure phase of the oscillations (FIG.14C), the balloon pressure is reduced to near the minimum pressureneeded to achieve balloon inflation, typically 1-2 atm. In thehigh-pressure phase of the oscillations (FIG. 14D), the balloon isinflated to a peak pressure, which can be set by the physician orsystem. Typical peak inflation pressures may be from above thelow-pressure range to the balloons' max rated pressure, which could be25 atm or more. Pressure cycling of the balloon in this manner inducescyclical loading of the calcified plaque 1450 below the calcifiedplaque's rupture stress yet in the plastic deformation zone. Theheterogeneity of the calcified plaque interior is composed of manymicrofractures with sharp corners. Through the fracture mechanismsdescribed herein, the cyclic loading described in FIGS. 14A-14E causescyclic stresses at these sharp corners near plaque microfractures andirregular surfaces. The cyclic stress initiates and grows these sharpcorners, which expand the microfractures into larger macroscopicfractures. The growth of these microfractures leads to the more completefracture of plaque at lower inflation pressures compared to staticpressure. Higher frequency pressure cycles and higher-pressuredifferences between the cycles is expected to increase the effectivenessof this crack growth mechanism. By generating controlled high-frequencypressures cycles in an angioplasty balloon, DBA lowers the requiredballoon pressure for fracturing calcified plaque (e.g., in someinstances between 1 to 50%, such as 20 to 30%, as compared to a suitablenon-DBA control), improves stent deployment, improves and controls drugdelivery for drug-coated balloons, stress-softens soft, lipid-coreatheromatous plaques, expands calcified in-stent restenoses, andfracture calcifications on diseased cardiac valve leaflets and improvesballoon-based expansion and deployment of prosthesis and devices.Further details regarding embodiments of DBA methods in which thesystems described herein may be employed are provided in United StatesPublished Patent Application Publication No. 20200046949 as well aspending PCT Application Serial No. PCT/US2020/055458; the disclosures ofwhich are herein incorporated by reference.

In some instances, systems of the invention, e.g., as described above,are employed in a manner sufficient to achieve a four-part pulsatiletreatment plan, e.g., as illustrated in FIG. 15, which four-partpulsatile treatment plan provides for safe, controlled expansion ofhardened plaques and surrounding healthy soft tissues. To treat thesemulti-compositional vessels, a four-part treatment algorithm may beemployed, which four-part treatment algorithm includes the followingsteps: (1) soft-tissue low-stress expansion phase 3800 via Mullins'Effect; (2) plastic deformation phase 3700 in the calcified plaque untilplaque fracture; (3) plaque fracture detection and immediate reductionin pressure phase 3600 to reduce surrounding tissue stress; and (4)soft-tissue low-stress expansion phase 3500 via Mullins' Effect toexpand soft-tissue post-calcium fracture. An embodiment in which theforce applied to the vessel over time by this four-part algorithm isillustrated in FIG. 6. Because of the significant attenuation across thecatheter and the lack of pressure control in prior art approaches, theinput pressure to the catheter is not successfully transmitted to theballoon (the system output). Therefore, tissue stress in prior artsystems is not returned to a low state (i.e., there is no tissuerelaxation period) during high frequency oscillation, which limits theeffect of Mullins' stress cycling. Through attenuation minimization andpressure control, the present system induces pressure oscillations inthe balloon (the system output) that follows the pressure input from theproximal source with pressure oscillations between 0-50 ATM, frequenciesbetween 0-25 Hz, and duty cycles between 60-80%. This advancement isimportant for two reasons: (1) it allows the tissue to relax during thedepressurization cycle (following the Mullins' Effect) and (2) it allowssufficient oscillations to be applied to the vessel within the limitedtime during which an artery is occluded during treatment. Furtherdetails regarding methods in which embodiments of the invention may beused are found in pending PCT application serial no. PCT/US2020/055458;the disclosure of which is herein incorporated by reference.

In certain instances, embodiments of the present invention may beapplied to assess vessel compliance. Blood vessels are naturallycompliant, elastic structures. Their compliance is required to convertthe pulsatile flow from the heart into steady flow in the capillaries.Over time, however, the aging and atherosclerotic process can diminishthe compliance of vessels and reduce lumen area, creating flowmismatches and additional stress to the vascular system. Vesselcompliance is especially diminished during and after the formation ofintimal and medial calcified plaque in the vessel wall.

Improving vessel compliance is a prerequisite to a more definitivetreatment of atherosclerosis. See Dattilo R, Himmelstein S I, Cuff R F.The COMPLIANCE 360° Trial: a randomized, prospective, multicenter, pilotstudy comparing acute and long-term results of orbital atherectomy toballoon angioplasty for calcified femoropopliteal disease. J InvasiveCardiol. 2014; 26(8):355-360.http://www.ncbi.nlm.nih.gov/pubmed/25091093. To maximize vessel wallcompliance after calcium buildup, angioplasty or intravascularlithotripsy therapy can be used to shatter intimal and medial calciumrings to expose the more elastic components of the tubular vessel and torelease it from the mummifying calcium. As noted above, embodiments ofthe present invention may be used to apply pulsatile intravascularlithotripsy enabling both for cracking of calcium (i.e., cracking CPtissue as shown in FIG. 14) as well as to apply a final post-dilatationof the vessel. In some cases, embodiments of the present invention mayapply both applications, cracking CP tissue and applying a finalpost-dilation of the tissue, in a single treatment. That is, embodimentsof the present invention can also be used to apply DBA first to applypulses to a vessel to crack CP tissue and then to subsequently expandthe vessel using, for example, a traditional, non-compliant balloonpost-dilatation.

By vessel compliance, it is meant a measurable quantity defined by thefollowing relationship:

$C = \frac{\Delta V}{\Delta P}$

where ΔV is the change in vessel volume for a given change in pressureΔP. Because of tissue incompressibility, vessel volume can be convertedto area by dividing by vessel length. Since the pressure-volumerelationship in an artery is non-linear, compliance is often defined ata given pressure or volume.

Vessel compliance can be difficult to obtain because simultaneousin-vivo measurements of pressure change, ΔP, and vessel cross-sectionalarea or volume change, ΔA or ΔV, respectively, may be challenging.Systems according to the present invention find use in addressing thisdifficulty by accurately assessing vessel compliance in-vivo asdescribed below.

As reviewed above, the proximal connector of the catheter balloonassembly may include a membrane positional sensor, such as a Hallsensor, which provides data regarding the spatial position of themembrane at any given time, as well as a pressure gauge for measuringpressure in the liquid passages and distal balloon of the ballooncatheter assembly. In such instances, the systems may be employed toassess volume expansion of the balloon in real time, and/or vesselcompliance at the site of the balloon.

As a consequence of measuring the diaphragm (i.e., membrane) position,the change in volume in the balloon can be assessed in real time and thecorresponding balloon pressure can be measured. That is, the system isconfigured to pressurize the balloon-based catheter while simultaneouslyreading pressure and volume in the catheter system. This volume-pressurerelationship can provide a measure of vessel compliance, since, asdescribed above, vessel compliance is the ratio of a change of vesselvolume to a change in pressure. To enable this measurement, the balloonvolume-pressure relationship can be measured when the balloon isuninhibited by a surrounding vessel. When located within a stiff vessel,the balloon requires a higher pressure for the equivalent balloon volumein its uninhibited, baseline state. Therefore, the balloon may be usedto measure compliance of the vessel. With the ability to accuratelyrecord diaphragm position (a surrogate measurement for balloon volume)and balloon pressure, the compliance of the vessel can be measuredeasily in-vivo. This compliance measure can be used as a measure of asuccessful treatment with a lower compliance indicating adequate ortherapeutic balloon expansion and a successful treatment. In someinstances, the system is employed in methods analogous to thosedescribed in U.S. Published Application Publication No. 20150080747 (thedisclosure of which is herein incorporated by reference), where membranedisplacement is used as the measure of balloon volume.

Systems and methods for measuring vessel compliance according to thepresent invention may be configured to obtain pre-, during, andpost-treatment pressure-volume measurements. Using the data obtainedduring these measurements, change in vessel compliance can be obtainedto determine treatment efficacy. Change in vessel compliance may also beused to adjust therapeutic intensity and/or duration.

In addition, embodiments of the present invention may be used togenerate pressure-volume (i.e., compliance curves) at various instancesduring treatment. A relative change in compliance pre- andpost-treatment may be obtained. These changes may be compared amongstsimilar vessel segments to understand an appropriate level of compliancechange.

In addition, methods according to the present invention may alsocomprise obtaining concomitant measures of intraarterial cross-sectionusing other available measuring techniques such as ultrasound,cineangiography, computed tomography, intravascular ultrasound (IVUS),and/or optical coherence tomography (OCT). In some instances, systemsaccording to the present invention may be configured to incorporateinformation obtained from such measurements, i.e., sensor fusiontechniques. Volume and/or area measurements obtained through suchvisualization techniques may be combined with pressure and volumereadings of embodiments of a balloon system according to the presentinvention (i.e., measurements of changes or relative volume and/orpressure) to generate absolute compliance measurements of vessels withincreased accuracy. Such absolute compliance measurements may then beused to compare treatments across vascular beds for optimizingtreatments for both short- and long-term success. In addition, anabsolute measure of the compliance curve of a vessel may be obtained andcompared across treatment groups.

While systems and methods of measuring vessel compliance have beendescribed in the context of pulsatile balloon catheter systems accordingto the present invention, such systems and methods for measuring vesselcompliance may be applied to other systems as well, such as systemsconfigured to deliver static balloon angioplasty, pulsatileintravascular lithotripsy, cavitation-based intravascular lithotripsy,and/or externally-applied lithotripsy pulses.

FIG. 16 shows the procedural steps of an autonomous angioplastyprocedure performed with the embodiments described above. To initiatethis autonomous procedure, the physician or technician in the sterilefield may connect the proximal connector to the actuator of the embodiedsystem. This step may involve some human interaction with the patientbut, fluoroscopy may be paused to minimize operator exposure. In thisembodiment, a robotic catheterization device (such as those known in theart may) be used to insert the angioplasty balloon across the lesion.This step may include fluoroscopy imaging and radiation but can beperformed from within a shielded lab, eliminating operator radiationexposure. Once the appropriate balloon is across the lesion, theoperator may choose the appropriate treatment setting and then initiatethe treatment. Prior to, during, or after the procedure, the operatormay visualize the fluoroscopy images and compare those images with themeasure pressure-volume data. If the treatment is not successful, theprocedure may be continued with the same or different settings. If thetreatment is unsuccessful, the balloon catheter may be removedrobotically. During these steps, the operator may remain inside theshielded lab and protected from radiation. In some instances, thepre-filled and/or spring-biased balloon catheter and/or a compositeballoon may be used to minimize radiation exposure of the operator. Inthese instances, the operator does not have to fill the catheter withcontrast solution, nor does s/he have to remove and collapse the balloonon procedure completion. Once all of these steps are performed andfluoroscopy is no longer needed, the procedure may be finalized.

FIG. 17 shows a graphical user interface (GUI) that the operator mayinterface with during the autonomous angioplasty procedure. In thisembodiment, the GUI may have several information zones such as aTreatment Characteristics zone, Balloon Characteristics zone, andPlotting zone. The Treatment Characteristics zone indicates theimportant procedural characteristics that the operator employs duringthe procedure. Such characteristics include pressure, frequency, dutycycle, cycle number, and procedure time. Some or all of thesecharacteristics may be updated or changed by the system and/or by theuser. The Balloon Characteristics zone may include information regardingthe balloon that has been attached to the handheld actuator. Informationthat may be displayed includes balloon diameter, length, nominalpressure, and rated pressure, and other balloon characteristics, such asdrug-coated or stent covered balloons. Additionally, balloon catheterconnectivity information (i.e., whether a balloon has been connected ornot) can be included in this section. In the Plot zone, variousprocedural plots may be displayed including a compliance plot andtreatment plot. The compliance plot may include a nominalpressure-volume curve that may be provided with the balloon.Additionally, a pressure-volume curve measured in-situ during theprocedure may be plotted and updated throughout the procedure. Theoperator may use this plot to determine treatment effect as a measure ofcompliance or efficacy. The pressure plot may include a display ofpressure versus time. Other information that may be included (not shown)on the GUI include treatment status and intensity, ON/OFF switches,indicator LEDs, and the like.

The systems may be used to apply pulsatile energy to internal tissuelocations of any number of different subjects. In some instances, thesubjects are “mammals” or “mammalian,” where these terms are usedbroadly to describe organisms which are within the class mammalia,including the orders carnivore (e.g., dogs and cats), rodentia (e.g.,mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees,and monkeys). In some instances, the subjects are humans.

Kits

Also provided are kits that include systems, or one or more componentsthereof, e.g., as described above. As such, kits may include, in someinstances, one or more of, balloon catheter assemblies, which may or maynot be prefilled, pulse generators, or components thereof, e.g.,hand-held actuators thereof, etc. The kit components may be present inpackaging, which packaging may be sterile, as desired.

Also present in the kit may be instructions for using the kitcomponents. The instructions may be recorded on a suitable recordingmedium. For example, the instructions may be printed on a substrate,such as paper or plastic, etc. As such, the instructions may be presentin the kits as a package insert, in the labeling of the container of thekit or components thereof (i.e., associated with the packaging orsub-packaging) etc. In other embodiments, the instructions are presentas an electronic storage data file present on a suitable computerreadable storage medium, e.g., portable flash drive, DVD- or CD-ROM,etc. The instructions may take any form, including complete instructionsfor how to use the device or as a website address with whichinstructions posted on the world wide web may be accessed.

The following example(s) is/are offered by way of illustration and notby way of limitation.

EXAMPLES

FIG. 18 provides a picture of a balloon catheter assembly according toan embodiment of the invention. FIG. 19 shows the assembly process forthe proximal connector of the balloon catheter assembly shown in FIG.18. The first step of the assembly process is to fix the electronicflexible printed circuit board assembly to the diaphragm and pressuresensor. For example, epoxy and solder, respectively, may be used. Thepressure sensor and diaphragm may be fixed to the distal flange. Usingan appropriate fixation technique (e.g., fasteners, welding, etc.), theproximal flange may be fixed to the distal flange. The electronicconnector may be fixed to the front face of the proximal flange withepoxy, for example, so as to provide a reliable connection to thehand-held actuator. FIG. 6 represents testing performed on the describedembodiment and physical assembly. The pressure is shown to increasewhile the force at the distal balloon increases as well. The forceproduced during oscillation matches the force produced during staticinflation, indicating minimal attenuation by the system duringpulsation. FIG. 20 provides a picture of a balloon catheter systemaccording to an embodiment of the invention, such as a balloon cathetersystem comprising an embodiment of a balloon catheter assembly shown inFIG. 18.

Embodiments of the invention provide a number of advantages, whichadvantages include, but are not limited to:

-   -   with the pre-filled balloon catheter and composite balloon        embodiments, the operator does not have to fill the balloon        catheter with a contrast/saline mixture, which is an improvement        since the amount of fluid that may be introduced by the        clinician at the time of treatment may be variable, there may be        errors in volume insertion, debubbling, deflating, etc.;    -   if the balloon is not pre-filled, the diaphragm tracking        mechanism provides a method of measuring the appropriate volume        inserted into the system;    -   with the pre-filled balloon catheter and composite balloon        embodiments, the volume-pressure relationship in the balloon can        be pre-measured and can be used to make decisions during        treatment;    -   embodiments allow for angioplasty pressurizations to be        performed with minimal physician interactions, thereby limiting        physician exposure to dangerous X-rays from fluoroscopy    -   the balloon may have an internal memory, which informs the rest        of the system of the potential treatment characteristics.

In at least some of the previously described embodiments, one or moreelements used in an embodiment can interchangeably be used in anotherembodiment unless such a replacement is not technically feasible. Itwill be appreciated by those skilled in the art that various otheromissions, additions and modifications may be made to the methods andstructures described above without departing from the scope of theclaimed subject matter. All such modifications and changes are intendedto fall within the scope of the subject matter, as defined by theappended claims.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseone having skill in the art would understand the convention (e.g., “asystem having at least one of A, B, and C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). It will be further understood by those withinthe art that virtually any disjunctive word and/or phrase presenting twoor more alternative terms, whether in the description, claims, ordrawings, should be understood to contemplate the possibilities ofincluding one of the terms, either of the terms, or both terms. Forexample, the phrase “A or B” will be understood to include thepossibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible sub-rangesand combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into sub-ranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 articles refers to groupshaving 1, 2, or 3 articles. Similarly, a group having 1-5 articlesrefers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. Moreover, nothing disclosedherein is intended to be dedicated to the public regardless of whethersuch disclosure is explicitly recited in the claims.

The scope of the present invention, therefore, is not intended to belimited to the exemplary embodiments shown and described herein. Rather,the scope and spirit of present invention is embodied by the appendedclaims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) isexpressly defined as being invoked for a limitation in the claim onlywhen the exact phrase “means for” or the exact phrase “step for” isrecited at the beginning of such limitation in the claim; if such exactphrase is not used in a limitation in the claim, then 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) is not invoked.

What is claimed is:
 1. A pulsatile balloon catheter system, the systemcomprising: (a) a pulse generator; and (b) a balloon catheter assemblyoperably connected to the pulse generator, the balloon catheter assemblycomprising: (i) a proximal connector operably connecting the ballooncatheter assembly to the pulse generator and configured to transduce afirst pulse energy generated by the pulse generator to a second pulseenergy; (ii) a distal balloon; and (iii) a catheter component comprisinga fluidic passage operably positioned between the proximal connector andthe distal balloon configured to propagate the second pulse energy fromthe proximal connector along the fluid passage to the distal balloon. 2.The pulsatile balloon catheter system according to claim 1, wherein theproximal connector comprises a proximal chamber and a distal chamberseparated by a membrane.
 3. The pulsatile balloon catheter systemaccording to claim 2, wherein the proximal chamber is defined by aproximal flange and the distal chamber is defined by a distal flange. 4.The pulsatile balloon catheter system according to claim 3, wherein theproximal flange comprises a proximal port configured to receive thefirst pulse energy generated by the pulse generator.
 5. The pulsatileballoon catheter system according to any of claims 2 to 4, wherein thedistal flange comprises a distal port fluidically coupling the distalchamber with the fluidic passage.
 6. The pulsatile balloon cathetersystem according to any of claims 2 to 5, wherein the proximal chambercomprises a gas and the distal chamber comprises a liquid.
 7. Thepulsatile balloon catheter system according to any of claims 2 to 6,wherein proximal connector further comprises a pressure sensor operablycoupled to the distal chamber.
 8. The pulsatile balloon catheter systemaccording to any of claims 2 to 7, wherein the proximal connectorcomprises a membrane positional sensor configured to detect changes inmembrane position of the membrane.
 9. The pulsatile balloon cathetersystem according to claim 8, wherein the membrane positional sensorcomprises a Hall Sensor.
 10. The pulsatile balloon catheter systemaccording to claim 9, wherein the pulse generator comprises a fixedmagnet positioned to modulate voltage of the Hall Sensor upon membranemovement.
 11. The pulsatile balloon catheter system according to any ofthe preceding claims, wherein the proximal connector further comprisesan electrical assembly.
 12. The pulsatile balloon catheter systemaccording to claim 11, wherein the electrical assembly comprisescircuitry.
 13. The pulsatile balloon catheter system according to claim11 or 12, wherein the electrical assembly comprises memory.
 14. Thepulsatile balloon catheter system according to claim 13, wherein thememory comprises distal balloon information.
 15. The pulsatile ballooncatheter system according to claim 14, wherein the distal ballooninformation comprises one or more of: expiration date, batch number,balloon size, balloon rated burst and nominal pressure, cycle limit, andcycles used for.
 16. The pulsatile balloon catheter system according toany of claims 11 to 15, wherein the proximal connector further comprisesan electrical connector electrically coupling the electrical assembly tothe pulse generator.
 17. The pulsatile balloon catheter system accordingto any of the preceding claims, wherein the catheter componentcomprises: a proximal flexible tube; a distal catheter shaft; and aconnector connecting the distal end of the proximal flexible tube to theproximal end of the distal catheter shaft.
 18. The pulsatile ballooncatheter system according to claim 17, wherein the connector comprises afirst branch configured to provide guidewire access to a guidewirechannel of the catheter shaft and a second branch configured tofluidically couple lumens of the proximal flexible tube and distalcatheter shaft.
 19. The pulsatile balloon catheter system according toclaim 18, wherein the connector is a Y connector.
 20. The pulsatileballoon catheter system according to any of the preceding claims,wherein the distal end balloon comprises a composite balloon.
 21. Thepulsatile balloon catheter system according to claim 20, wherein thecomposite balloon comprises a compliant component and a non-compliantcomponent.
 22. The pulsatile balloon catheter system according to any ofthe preceding claims, where the balloon catheter assembly comprises asealed assembly filled with a predetermined volume of liquid.
 23. Thepulsatile balloon catheter system according to claim 22, wherein theliquid comprises a contrast agent.
 24. The pulsatile balloon cathetersystem according to any of the preceding claims, wherein pulse generatoris configured to generate pneumatic pulse energy.
 25. The pulsatileballoon catheter system according to any of the preceding claims,wherein the pulse generator comprises a hand-held actuator operablyconnected to the proximal connector.
 26. The pulsatile balloon cathetersystem according to any of the preceding claims, wherein the pulsegenerator is reusable.
 27. The pulsatile balloon catheter systemaccording to any of the preceding claims, wherein the balloon catheterassembly is configured for single use.
 28. The pulsatile ballooncatheter system according to claim 1, wherein the system is configuredto produce a pressure pulse having an amplitude that is selected basedon treatment efficacy.
 29. The pulsatile balloon catheter systemaccording to claim 28, wherein the treatment efficacy is assessed byvolume change in the balloon.
 30. The pulsatile balloon catheter systemaccording to claim 28, wherein the volume change in the balloon isdetermined by diaphragm position.
 31. The pulsatile balloon cathetersystem according to any of claims 1 to 30, further configured to assessvessel compliance.
 32. The pulsatile balloon catheter system accordingto claim 31, wherein the system further comprises a membrane positionalsensor configured to detect changes in position of the membrane, whereinthe system is further configured to assess vessel compliance based onchanges in pressure detected by the pressure sensor and changes involume based on changes in position of the membrane.
 33. The pulsatileballoon catheter system according to claim 32, wherein the membranepositional sensor comprises a Hall Sensor.
 34. The pulsatile ballooncatheter system according to claim 33, further comprising a fixed magnetpositioned to modulate voltage of the Hall Sensor upon membranemovement.
 35. The pulsatile balloon catheter system according to any ofclaims 31 to 34, further configured to assess vessel compliancesubstantially in real time during treatment.
 36. The pulsatile ballooncatheter system according to any of claims 31 to 35, further configuredto assess vessel compliance before and after treatment.
 37. Thepulsatile balloon catheter system according to any of claims 31 to 36,wherein treatment efficacy is assessed based on changes in vesselcompliance.
 38. The pulsatile balloon catheter system according to anyof the preceding claims, further configured to detect system states. 39.The pulsatile balloon catheter system according to claim 38, furthercomprising an electronic circuit configured to detect system states. 40.The pulsatile balloon catheter system according to claim 39, wherein theelectronic circuit is configured to compare a measured systemcharacteristic to a target threshold.
 41. The pulsatile balloon cathetersystem according to claim 40, wherein the measured system characteristiccomprises pressure.
 42. The pulsatile balloon catheter system accordingto claim 41, wherein the measured pressure is catheter pressure.
 43. Thepulsatile balloon catheter system according to claim 42, wherein themeasured catheter pressure is a maximal amplitude of pulsatile catheterpressure.
 44. The pulsatile balloon catheter system according to claim41, wherein the measured system characteristic comprises volume.
 45. Thepulsatile balloon catheter system according to claim 44, wherein themeasured volume is distal balloon volume.
 46. The pulsatile ballooncatheter system according to claim 45, wherein the measured distalballoon volume is a maximal distal balloon volume.
 47. The pulsatileballoon catheter system according to any of claims 40 to 46, wherein theelectronic circuit comprises: a comparator circuit, configured tocompare the measured system characteristic against the target threshold;and a flip-flop, configured to store the result of the comparatorcircuit, wherein the flip-flop is clocked based on a pressure controlsignal, and the stored data value of the flip-flop reflects systemstate.
 48. The pulsatile balloon catheter system according to claim 47,wherein the circuit is configured to write a result of the comparatorcircuit to the flip-flop so that the result substantially corresponds toa comparison of maximal amplitude catheter pressure or maximal distalballoon volume.
 49. The pulsatile balloon catheter system according toany of claims 47 to 48, wherein the pressure control signal is based ona catheter pressure control signal.
 50. The pulsatile balloon cathetersystem according to claim 49, wherein the catheter pressure controlsignal is a solenoid trigger signal.
 51. The pulsatile balloon cathetersystem according to claim 50, wherein the circuit is configured to writethe result of the comparator circuit to the flip-flop upon the trailingedge of the solenoid trigger signal.
 52. The pulsatile balloon cathetersystem according to any of claims 38 to 51, wherein the detected systemstate is one or more of a pressure fault, a system leak, or a balloonburst.
 53. A system for transmitting pulse energy through a fluidicpassage of a catheter, the system comprising: (a) a plurality ofpulse-generating assemblies, wherein each pulse-generating assemblycomprises: (i) a pulse generator; and (ii) a proximal connector operablyconnected to the pulse generator and configured to transduce a firstpulse energy generated by the pulse generator to a second pulse energy;(b) a catheter component comprising a fluidic passage, wherein thefluidic passage is operably positioned between the proximal connectorsand a distal balloon and configured to propagate each second pulseenergy from each proximal connector along the fluid passage; and (c) acontroller configured to control the plurality of pulse-generatingassemblies, wherein the controller and the plurality of pulse-generatingassemblies are configured so that the controller independently controlseach pulse generator of the plurality of pulse-generating assemblies.54. A system for transmitting pulse energy through a plurality offluidic passages, the system comprising: (a) a pulse generator; (b) aproximal connector operably connected to the pulse generator andconfigured to transduce a first pulse energy generated by the pulsegenerator to a second pulse energy; (c) a plurality of fluidic passages,wherein each fluidic passage is configured to propagate the second pulseenergy from the proximal connector along each fluidic passage; and (d) acontroller configured to control the pulse generator, wherein thecontroller and the pulse generator are configured so that the controllercontrols a potential output of the pulse generator.
 55. A method ofimparting pulsatile energy to an internal luminal tissue location, themethod comprising: deploying a pulsatile balloon catheter systemaccording to any of claims 1 to 52 so that the distal balloon isadjacent to the internal luminal tissue location, and actuating thesystem to impart pulsatile energy to the internal luminal tissuelocation.
 56. The method according to claim 55, wherein the method is amethod of performing dynamic balloon angioplasty.
 57. The methodaccording to claims 55 and 56, wherein the method is a method ofassessing vessel compliance.
 58. A method of assessing vessel complianceof an internal luminal tissue location with a balloon catheter system,wherein the balloon catheter system comprises a distal balloon connectedto a catheter component, the method comprising: deploying the ballooncatheter system so that the distal balloon is adjacent to the internalluminal tissue location; actuating the balloon catheter system to applypressure to the distal balloon through the catheter component; detectinga change in volume of the distal balloon and substantiallysimultaneously detecting a change pressure applied to the distal balloonthrough the catheter component; and assessing vessel compliance of theinternal luminal tissue location based on the detected change in volumeand the detected change in pressure.
 59. The method of assessing vesselcompliance according to claim 58, wherein vessel compliance of theinternal luminal tissue location is measured substantially in real timeduring treatment.
 60. The method of assessing vessel complianceaccording to any of claims 58 to 59, further comprising measuring vesselcompliance of the internal luminal tissue location at different timesduring treatment.
 61. The method of assessing vessel complianceaccording to claim 58, further comprising assessing vessel compliance ofthe internal luminal tissue location before and after treatment.
 62. Themethod of assessing vessel compliance according to any of claims 58 to61, further comprising measuring absolute vessel compliance of theinternal luminal tissue location.
 63. The method of assessing vesselcompliance according to claim 62, wherein absolute vessel compliance isdetermined based on measuring a cross-sectional area of the internalluminal tissue.
 64. The method of assessing vessel compliance accordingto claim 63, wherein measuring a cross-sectional area of the internalluminal tissue comprises applying one or more of fluoroscopy,intravascular ultrasound, or optical coherence tomography techniques.65. A method comprising: deploying a system so that a distal balloon ofthe system is adjacent to an internal luminal tissue location, thesystem comprising: (a) a plurality of pulse-generating assemblies,wherein each pulse-generating assembly comprises: (i) a pulse generator;and (ii) a proximal connector operably connected to the pulse generatorand configured to transduce a first pulse energy generated by the pulsegenerator to a second pulse energy; (b) a catheter component comprisinga fluidic passage, wherein the fluidic passage is operably positionedbetween the proximal connectors and a distal balloon and configured topropagate each second pulse energy from each proximal connector alongthe fluid passage; and (c) a controller configured to control theplurality of pulse-generating assemblies, wherein the controller and theplurality of pulse-generating assemblies are configured so that thecontroller independently controls each pulse generator of the pluralityof pulse-generating assemblies; and actuating the system to impartpulsatile energy to the internal luminal tissue location.
 66. A methodcomprising: deploying a system so that a distal balloon of the system isadjacent to an internal luminal tissue location, the system comprising:(a) a pulse generator; (b) a proximal connector operably connected tothe pulse generator and configured to transduce a first pulse energygenerated by the pulse generator to a second pulse energy; (c) aplurality of fluidic passages, wherein each fluidic passage isconfigured to propagate the second pulse energy from the proximalconnector along each fluidic passage; and (d) a controller configured tocontrol the pulse generator, wherein the controller and the pulsegenerator are configured so that the controller controls a potentialoutput of the pulse generator; and actuating the system to impartpulsatile energy to the internal luminal tissue location.
 67. A ballooncatheter assembly comprising: (a) a proximal connector operablyconnecting the balloon catheter assembly to the pulse generator andconfigured to transduce a first pulse energy generated by the pulsegenerator to a second pulse energy; (b) a distal balloon; and (c) acatheter component comprising a fluidic passage operably positionedbetween the proximal connector and the distal balloon configured topropagate the second pulse energy from the proximal connector along thefluid passage to the distal balloon.
 68. The balloon catheter assemblyaccording to claim 67, wherein the proximal connector comprises aproximal chamber and a distal chamber separated by a membrane.
 69. Theballoon catheter assembly according to claim 68, wherein the proximalchamber is defined by a proximal flange and the distal chamber isdefined by a distal flange.
 70. The balloon catheter assembly accordingto claim 69, wherein the proximal flange comprises a proximal portconfigured to receive the first pulse energy generated by the pulsegenerator.
 71. The balloon catheter assembly according to any of claims68 to 70, wherein the distal flange comprises a distal port fluidicallycoupling the distal chamber with the fluidic passage.
 72. The ballooncatheter assembly according to any of claims 68 to 71, wherein theproximal chamber comprises a gas and the distal chamber comprises aliquid.
 73. The balloon catheter assembly according to any of claims 68to 72, wherein proximal connector further comprises a pressure sensoroperably coupled to the distal chamber.
 74. The balloon catheterassembly according to any of claims 68 to 73, wherein the proximalconnector comprises a membrane positional sensor configured to detectchanges in membrane position of the membrane.
 75. The balloon catheterassembly according to claim 74, wherein the membrane positional sensorcomprises a Hall Sensor.
 76. The balloon catheter assembly according toany of claims 67 to 75, wherein the proximal connector further comprisesan electrical assembly.
 77. The balloon catheter assembly according toclaim 76, wherein the electrical assembly comprises circuitry.
 78. Theballoon catheter assembly according to any of claims 76 to 77, whereinthe electrical assembly comprises memory.
 79. The balloon catheterassembly according to claim 78, wherein the memory comprises distalballoon information.
 80. The balloon catheter assembly according toclaim 79, wherein the distal balloon information comprises one or moreof: expiration date, batch number, balloon size, balloon rated burst andnominal pressure, cycle limit, and cycles used for.
 81. The ballooncatheter assembly according to any of claims 76 to 80, wherein theproximal connector further comprises an electrical connectorelectrically coupling the electrical assembly to a pulse generator. 82.The balloon catheter assembly according to any of claims 67 to 81,wherein the catheter component comprises: a proximal flexible tube; adistal catheter shaft; and a connector connecting the distal end of theproximal flexible tube to the proximal end of the distal catheter shaft.83. The balloon catheter assembly according to claim 82, wherein theconnector comprises a first branch configured to provide guidewireaccess to a guidewire channel of the catheter shaft and a second branchconfigured to fluidically couple lumens of the proximal flexible tubeand distal catheter shaft.
 84. The balloon catheter assembly accordingto claim 83, wherein the connector is a Y connector.
 85. The ballooncatheter assembly according to any of claims 67 to 84, wherein thedistal end balloon comprises a composite balloon.
 86. The ballooncatheter assembly according to claim 85, wherein the composite ballooncomprises a compliant component and a non-compliant component.
 87. Theballoon catheter assembly according to any of claims 67 to 86, where theballoon catheter assembly comprises a sealed assembly filled with apredetermined volume of liquid.
 88. The balloon catheter assemblyaccording to claim 87, wherein the liquid comprises a contrast agent.89. The balloon catheter assembly according to any of claims 67 to 88,wherein the balloon catheter assembly is configured for single use. 90.The balloon catheter assembly according to any of claims 67 to 89,further configured to assess vessel compliance.
 91. The balloon catheterassembly according to claim 73, wherein the system further comprises amembrane positional sensor configured to detect changes in position ofthe membrane, wherein the system is further configured to assess vesselcompliance based on changes in pressure detected by the pressure sensorand changes in volume based on changes in position of the membrane. 92.The balloon catheter assembly according to claim 91, wherein themembrane positional sensor comprises a Hall Sensor.
 93. The ballooncatheter assembly according to claim 92, further comprising a fixedmagnet positioned to modulate voltage of the Hall Sensor upon membranemovement.
 94. The balloon catheter assembly according to any of claims90 to 93, further configured to assess vessel compliance substantiallyin real time during treatment.
 95. The balloon catheter assemblyaccording to any of claims 90 to 94, further configured to assess vesselcompliance before and after treatment.
 96. The balloon catheter assemblyaccording to any of claims 90 to 95, wherein treatment efficacy isassessed based on changes in vessel compliance.
 97. The balloon catheterassembly according to any of claims 67 to 96, further configured todetect system states.
 98. The balloon catheter assembly according toclaim 97, further comprising an electronic circuit configured to detectsystem states.
 99. The balloon catheter assembly according to claim 98,wherein the electronic circuit is configured to compare a measuredsystem characteristic to a target threshold.
 100. The balloon catheterassembly according to claim 99, wherein the measured systemcharacteristic comprises pressure.
 101. The balloon catheter assemblyaccording to claim 100, wherein the measured pressure is catheterpressure.
 102. The balloon catheter assembly according to claim 101,wherein the measured catheter pressure is a maximal amplitude ofpulsatile catheter pressure.
 103. The balloon catheter assemblyaccording to claim 99, wherein the measured system characteristiccomprises volume.
 104. The balloon catheter assembly according to claim103, wherein the measured volume is distal balloon volume.
 105. Theballoon catheter assembly according to claim 104, wherein the measureddistal balloon volume is a maximal distal balloon volume.
 106. Theballoon catheter assembly according to any of claims 99 to 105, whereinthe electronic circuit comprises: a comparator circuit, configured tocompare the measured system characteristic against the target threshold;and a flip-flop, configured to store the result of the comparatorcircuit, wherein the flip-flop is clocked based on a pressure controlsignal, and the stored data value of the flip-flop reflects systemstate.
 107. The balloon catheter assembly according to claim 106,wherein the circuit is configured to write a result of the comparatorcircuit to the flip-flop so that the result substantially corresponds toa comparison of maximal amplitude catheter pressure or maximal distalballoon volume.
 108. The balloon catheter assembly according to any ofclaims 106 to 107, wherein the pressure control signal is based on acatheter pressure control signal.
 109. The balloon catheter assemblyaccording to claim 108, wherein the catheter pressure control signal isa solenoid trigger signal.
 110. The balloon catheter assembly accordingto claim 109, wherein the circuit is configured to write the result ofthe comparator circuit to the flip-flop upon the trailing edge of thesolenoid trigger signal.
 111. The balloon catheter assembly according toany of claims 97 to 110, wherein the detected system state is one ormore of a pressure fault, a system leak, or a balloon burst.
 112. Aballoon catheter assembly comprising: (a) a plurality of proximalconnectors each operably connected to a pulse generator and configuredto transduce a first pulse energy generated by the pulse generator to asecond pulse energy; and (b) a catheter component comprising a fluidicpassage, wherein the fluidic passage is operably positioned between theproximal connectors and a distal balloon and configured to propagateeach second pulse energy from each proximal connector along the fluidpassage.
 113. A balloon catheter assembly comprising: (a) a proximalconnector operably connected to a pulse generator and configured totransduce a first pulse energy generated by the pulse generator to asecond pulse energy; and (b) a plurality of fluidic passages, whereineach fluidic passage is configured to propagate the second pulse energyfrom the proximal connector along each fluidic passage.
 114. A kitcomprising a balloon catheter assembly according to any of claims 67 to113.
 115. The kit according to claim 114, further comprising a pulsegenerator as claimed in any of claims 1 to
 54. 116. A pulsatile ballooncatheter system, the system comprising: (a) a pulse generator; and (b) aballoon catheter assembly operably connected to the pulse generator,wherein the system is configured to be operated remotely.
 117. Thepulsatile balloon catheter system according to claim 116, wherein thesystem is configured to provide procedure-based feedback information toa user.
 118. The pulsatile balloon catheter system according to claim117, where the procedure-based feedback information comprises one ormore of balloon pressure, volume change, procedural success and balloonfrequency.
 119. The pulsatile balloon catheter system according to anyone of claims 117 to 118, wherein the system is configured to providethe procedure-based feedback information to a user via one or more ofsound, visual and feel (e.g., vibration).
 120. The pulsatile ballooncatheter system according to any one of claims 116 to 119, wherein thesystem comprises a station for an operator to performing a procedureusing the system.
 121. The pulsatile balloon catheter system accordingto claim 120, wherein the station is shielded.
 122. The pulsatileballoon catheter system according to any one of claims 116 to 121,wherein the balloon catheter assembly comprises a catheter component anddistal balloon pre-filled with a liquid.
 123. The pulsatile ballooncatheter system according to claim 122, where the liquid comprisessaline or contrast liquid.
 124. The pulsatile balloon catheter systemaccording to any one of claims 116 to 123, wherein the balloon catheterassembly comprises a distal balloon that is configured to automaticallydeflate upon release of pressure.
 125. The pulsatile balloon cathetersystem according to claim 124, wherein the distal balloon comprises acomposite balloon.